Volibris

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Volibris uses


WARNING: EMBRYO-FETAL TOXICITY

Do not administer Volibris to a pregnant female because it may cause fetal harm. Volibris 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 Volibris. Females of reproductive potential must use acceptable methods of contraception during treatment with Volibris 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 Volibris through a restricted program called the Volibris REMS program .

WARNING: EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

  • Indications and Usage (1)
  • Dosage and Administration (2.1)
  • Warnings and Precautions (5.3)
  • 10/2015
  • 10/2015
  • 10/2015
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1 INDICATIONS AND USAGE

Volibris is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):


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%).

Volibris is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):


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).

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 Volibris or tadalafil can be increased, as needed and tolerated, to Volibris 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 Volibris in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment .

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3 DOSAGE FORMS AND STRENGTHS

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


Tablet: 5 mg and 10 mg (3)

4 CONTRAINDICATIONS

4.1 Pregnancy

Volibris may cause fetal harm when administered to a pregnant female. Volibris is contraindicated in females who are pregnant. Volibris 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 .

4.2 Idiopathic Pulmonary Fibrosis

Volibris is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) .

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-fetal Toxicity

Volibris 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 .

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

5.2 Volibris REMS Program

For all females, Volibris is available only through a restricted program called the Volibris REMS, because of the risk of embryo-fetal toxicity .

Notable requirements of the Volibris REMS program include the following:


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

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 Volibris compared to placebo . 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 Volibris. 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 Volibris or underlying heart failure, and the possible need for specific treatment or discontinuation of Volibris therapy.

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

5.4 Pulmonary Edema with Pulmonary Veno-occlusive Disease

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

5.5 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 Volibris. Volibris may have an adverse effect on spermatogenesis. Counsel patients about potential effects on fertility .

5.6 Hematological Changes

Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Volibris. These decreases were observed within the first few weeks of treatment with Volibris, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving Volibris 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 Volibris (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 Volibris, at one month, and periodically thereafter. Initiation of Volibris 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 Volibris.

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6 ADVERSE REACTIONS

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


To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at (1-800-445-3235, Option 3) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Volibris are presented from two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) in patients with pulmonary arterial hypertension (PAH), and one randomized, double-blind, active-controlled trial in 605 patients with PAH (AMBITION) comparing Volibris plus tadalafil to Volibris or tadalafil alone. The exposure to Volibris in these studies ranged from 1 day to 4 years (N=357 for at least 6 months and N=279 for at least 1 year).

In ARIES-1 and ARIES-2, a total of 261 patients received Volibris 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 Volibris than receiving placebo are shown in Table 1.

Placebo

(N=132)

Volibris

(N=261)

Adverse Reaction 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 Volibris (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving Volibris (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 Volibris (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 Volibris (5%; 13/261 patients).

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

Combination Use with Tadalafil

The mean exposure to Volibris + tadalafil in the AMBITION study was 78.7 weeks. The adverse reactions that occurred in >5% more patients receiving Volibris + tadalafil than receiving Volibris or tadalafil monotherapy in AMBITION are shown in Table 2.

Adverse Reactions Volibris + Tadalafil Combination Therapy

(N=302)

n (%)

Volibris Monotherapy

(N=152)

n (%)

Tadalafil Monotherapy

(N=151)

n (%)

Peripheral edema 135 (45%) 58 (38%) 43 (28%)
Headache 125 (41%) 51 (34%) 53 (35%)
Nasal congestion 58 (19%) 25 (16%) 17 (11%)
Cough 53 (18%) 20 (13%) 24 (16%)
Anemia 44 (15%) 11 (7%) 17 (11%)
Dyspepsia 32 (11%) 5 (3%) 18 (12%)
Bronchitis 31 (10%) 6 (4%) 13 (9%)

Peripheral edema was more frequent on combination therapy; however, there was no notable difference observed in the incidence of peripheral edema in elderly patients (≥65 years) versus younger patients (<65 years) on combination therapy (44% vs. 45%) or Volibris monotherapy (37% vs. 39%) in AMBITION.

Treatment discontinuations due to adverse events while on randomized treatment were similar across treatment groups: 16% for Volibris + tadalafil, 14% for Volibris alone, and 13% for tadalafil alone.

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 × ULN were treated with Volibris. Prior elevations were predominantly moderate, with 64% of the ALT elevations <5 × ULN, but 9 patients had elevations >8 × 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 × ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on Volibris 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 Volibris 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 Volibris led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that Volibris may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.

6.2 Postmarketing Experience

The following adverse reactions were identified during post-approval use of Volibris. 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 requiring transfusion heart failure (associated with fluid retention), symptomatic hypotension, and hypersensitivity (e.g., angioedema, rash).

Elevations of liver aminotransferases (ALT, AST) have been reported with Volibris 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 .

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7 DRUG INTERACTIONS

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

Cyclosporine increases Volibris exposure; limit Volibris dose to 5 mg once daily (7).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

Risk Summary

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

Animal Data

Volibris 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 Volibris from late gestation through weaning. The mid and high dosages were 51 ×, and 170 × (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 × the human dose based on mg/m2.

8.3 Nursing Mothers

It is not known whether Volibris 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 Volibris, a decision should be made whether to discontinue nursing or discontinue Volibris, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

In the two placebo-controlled clinical studies of Volibris, 21% of patients were ≥65 years old and 5% were ≥75 years old. The elderly showed less improvement in walk distances with Volibris 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.

8.6 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 Volibris. 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 .

Contraception

Female patients of reproductive potential must use acceptable methods of contraception during treatment with Volibris and for 1 month after stopping treatment with Volibris. 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 .

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 from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Volibris have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility .

8.7 Renal Impairment

The impact of renal impairment on the pharmacokinetics of Volibris 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 Volibris . Dose adjustment of Volibris in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to Volibris in patients with severe renal impairment.

The impact of hemodialysis on the disposition of Volibris has not been investigated.

8.8 Hepatic Impairment

Pre-existing Hepatic Impairment

The influence of pre-existing hepatic impairment on the pharmacokinetics of Volibris has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of Volibris, hepatic impairment might be expected to have significant effects on the pharmacokinetics of Volibris . Volibris is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of Volibris in patients with mild pre-existing impaired liver function; however, exposure to Volibris 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 . In patients who develop hepatic impairment after Volibris initiation, the cause of liver injury should be fully investigated. Discontinue Volibris if elevations of liver aminotransferases are >5 × ULN or if elevations are accompanied by bilirubin >2 × ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.

10 OVERDOSAGE

There is no experience with overdosage of Volibris. The highest single dose of Volibris 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.

11 DESCRIPTION

Volibris is the brand name for Volibris, an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. The chemical name of Volibris 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

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

Volibris 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 Volibris tablet contains 5 mg of Volibris. Each oval, deep pink Volibris tablet contains 10 mg of Volibris. Volibris tablets are unscored.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endothelin-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.

Volibris 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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

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

N-terminal pro-B-type natriuretic peptide (NT-proBNP)

In AMBITION , the decrease in NT-proBNP in patients on Volibris plus tadalafil was observed early (Week 4) and was sustained, with a reduction of 63% on Volibris plus tadalafil, 50% on Volibris alone, and 41% on tadalafil alone at Week 24.

12.3 Pharmacokinetics

The pharmacokinetics of Volibris (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of Volibris is not known. Volibris 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 Volibris is a substrate of P-gp. Volibris is highly bound to plasma proteins (99%). The elimination of Volibris 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 Volibris accounts for approximately 4% relative to parent Volibris AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of Volibris is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although Volibris has a 15-hour terminal half-life, the mean trough concentration of Volibris 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 Volibris is about 9 hours.

Drug Interactions

In Vitro Studies

Studies with human liver tissue indicate that Volibris is metabolized by CYP3A, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that Volibris 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 . In vitro studies found Volibris to have little to no inhibition of human hepatic transporters. Volibris 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. Volibris does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.

In Vivo Studies

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

Figure 2 Effects of Other Drugs on Volibris Pharmacokinetics

* 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 Volibris on Other Drugs

* Active metabolite of mycophenolate mofetil

** GMR (95% CI) for INR

Figure 2 Figure 3

13 NONCLINICAL TOXICOLOGY

13.1 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, Volibris 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 Volibris 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 Volibris 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 Volibris 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.

14 CLINICAL STUDIES

14.1 Pulmonary Arterial Hypertension

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 Volibris and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg Volibris to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg Volibris to placebo. In both studies, Volibris 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 3 and Figure 4.

ARIES-1 ARIES-2
Placebo

(N=67)

5 mg

(N=67)

10 mg

(N=67)

Placebo

(N=65)

2.5 mg

(N=64)

5 mg

(N=63)

Mean ± standard deviation
Baseline 342 ± 73 340 ± 77 342 ± 78 343 ± 86 347 ± 84 355 ± 84
Mean change from baseline -8 ± 79 23 ± 83 44 ± 63 -10 ± 94 22 ± 83 49 ± 75
Placebo-adjusted mean change from baseline 31 51 32 59
Placebo-adjusted median change from baseline 27 39 30 45
p-valuep-values are Wilcoxon rank sum test comparisons of Volibris to placebo at Week 12 stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients 0.008 <0.001 0.022 <0.001

Figure 4 Mean Change in 6-Minute Walk Distance (ARIES-1 and ARIES-2)

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

In both studies, treatment with Volibris resulted in a significant improvement in 6-minute walk distance for each dose of Volibris and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with Volibris, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with Volibris 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.

Figure 4

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 Volibris clinical trials are shown in Table 4 and Figure 5.

ARIES-1 ARIES-2
Placebo

(N=67)

Volibris

(N=134)

Placebo

(N=65)

Volibris

(N=127)

Intention-to-treat population.

Note: Patients may have had more than one reason for clinical worsening.

Nominal p-values

Clinical worsening, no. (%) 7 (10%) 4 (3%) 13 (22%) 8 (6%)
Hazard ratio 0.28 0.30
p-value, Log-rank test 0.030 0.005

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

Figure 5 Time to Clinical Worsening (ARIES-1 and ARIES-2)

Time from randomization to clinical worsening with Kaplan-Meier estimates of the proportions of patients without events in ARIES-1 and ARIES-2.

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

Figure 5

14.2 Combination Treatment of PAH

In a randomized, double-blind, active-controlled trial, 605 patients with WHO Functional Class II or III PAH were randomized 2:1:1 to once daily Volibris plus tadalafil or to Volibris or tadalafil alone. Treatment was initiated with Volibris 5 mg and tadalafil 20 mg. If tolerated, tadalafil was increased to 40 mg at 4 weeks and Volibris was increased to 10 mg at 8 weeks.

The primary endpoint was time to first occurrence of (a) death, (b) hospitalization for worsening PAH, (c) >15% decrease from baseline in 6MWD combined with WHO Functional Class III or IV symptoms sustained over 14 days (short term clinical worsening), or (d) reduction in 6MWD sustained over 14 days combined with WHO Functional Class III or IV symptoms sustained over 6 months (inadequate long term clinical response).

Patients had idiopathic PAH (55%), heritable PAH (3%), or PAH associated with connective tissue diseases, congenital heart disease, stable HIV infection, or drugs or toxins (APAH, 43%). Median time from diagnosis to first study drug administration was 25 days. Approximately 32% and 68% of patients were in WHO Functional Class II and III, respectively. The mean patient age was 55.7 years (34% were ≥65 years old). Most patients were white (90%) and female (76%); 45% were North American.

Principal results are shown in Figures 6 and 7.

Figure 6 Time to Primary Endpoint Event (AMBITION)

Figure 7 Primary Endpoint Events and First Occurrences of Each Component at Any Time (AMBITION)

The treatment effect of Volibris plus tadalafil compared with individual monotherapy on time to first primary endpoint event was consistent across subgroups. (Figure 8).

Figure 8 Primary Endpoint by Subgroups (AMBITION)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over interpreted.

Figure 6 Figure 7 Figure 8

Exercise Ability

Results of the 6MWD at 24 weeks for the AMBITION study are shown in Table 5 and Figure 9.

Volibris + Tadalafil

(N=302)

Volibris Monotherapy

(N=152)

Tadalafil Monotherapy

(N=151)

Baseline (median) 356 366 352
Change from baseline (median) 43 23 22
Median difference from Volibris + Tadalafil

(95% CI)

24

(11, 37)

20

(8, 32)

P-Value 0.0004 0.0016

Figure 9 Median Change in 6-Minute Walk Distance (meters) in AMBITION

Figure 9

14.3 Long-term Treatment of PAH

In long-term follow-up of patients who were treated with Volibris (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 Volibris 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 Volibris and cannot be used to determine the long-term effect of Volibris on mortality.

14.4 Adverse Effects in Idiopathic Pulmonary Fibrosis

A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared Volibris (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 Volibris. More patients taking Volibris died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%) .

16 HOW SUPPLIED/STORAGE AND HANDLING

Volibris 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 × 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 1530° C (5986° F) . Store Volibris in its original packaging.

17 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Embryo-fetal Toxicity

Instruct patients on the risk of fetal harm when Volibris is used in pregnancy . Female patients must enroll in the Volibris REMS program. Instruct females of reproductive potential to immediately contact their physician if they suspect they may be pregnant.

Volibris REMS Program

For female patients, Volibris is only available through a restricted program called the Volibris REMS . Male patients are not enrolled in the Volibris REMS.

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


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

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

Hepatic Effects

Advise patients of the symptoms of potential liver injury and instruct them to report any of these symptoms to their physician.

Hematological Change

Advise patients of the importance of hemoglobin testing.

Other Risks Associated with Volibris

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


Administration

Advise patients not to split, crush, or chew tablets.

Gilead Sciences, Inc., Foster City, CA 94404

Volibris is a registered trademark of Gilead Sciences, Inc. Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc. Other brands noted herein are the property of their respective owners.

© 2015 Gilead Sciences, Inc.

GS22-081-015-PI

Medication Guide

Volibris®

(ambrisentan) Tablets

Read this Medication Guide before you start taking Volibris 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 Volibris?


If you are the parent or caregiver of a female child who started taking Volibris before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your doctor right away if you notice that she is developing breast buds or pubic hair. Your doctor should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period.

Females can only receive Volibris through a restricted program called the Volibris Risk Evaluation and Mitigation Strategy (REMS) program. If you are a female who can get pregnant, you must talk to your doctor, understand the benefits and risks of Volibris, and agree to all of the instructions in the Volibris REMS program.

Males can receive Volibris without taking part in the Volibris REMS program.

What is Volibris?


Who should not take Volibris?

Do not take Volibris if:


What should I tell my doctor before taking Volibris?

Before you take Volibris, tell your doctor if you:


Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Volibris 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 Volibris.

How should I take Volibris?


What should I avoid while taking Volibris?


What are the possible side effects of Volibris?

Volibris can cause serious side effects including:


The most common side effects of Volibris include:

  • 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)

Some medicines that are like Volibris can cause liver problems. Tell your doctor if you get any of these symptoms of a liver problem while taking Volibris:

  • loss of appetite
  • nausea or vomiting
  • fever
  • achiness
  • generally do not feel well
  • pain in the upper right stomach (abdominal) area
  • yellowing of your skin or the whites of your eyes
  • dark urine
  • itching

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Volibris. For more information, ask your doctor or pharmacist.

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

How should I store Volibris?

Store Volibris at room temperature between 68°F to 77°F (20°C to 25°C), in the package it comes in.

Keep Volibris and all medicines out of the reach of children.

General information about the safe and effective use of Volibris

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Volibris for a condition for which it was not prescribed. Do not give Volibris to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Volibris. If you would like more information, ask your doctor. You can ask your doctor or pharmacist for information about Volibris that is written for health professionals.

What are the ingredients in Volibris?

Active ingredient: Volibris

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.

Gilead Sciences, Inc., Foster City, CA 94404

Volibris is a registered trademark of Gilead Sciences, Inc. Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc. Other brands noted herein are the property of their respective owners.

© 2015 Gilead Sciences, Inc.

GS22-081-014-MG

For more information call 1-866-664-5327 or go to www.letairis.com or www.gilead.com.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised October 2015

Chart

Volibris pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Volibris available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Volibris destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Volibris Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Volibris pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."LETAIRIS (AMBRISENTAN) TABLET, FILM COATED [GILEAD SCIENCES, INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."AMBRISENTAN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Ambrisentan". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Volibris?

Depending on the reaction of the Volibris after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Volibris not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Volibris addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Volibris, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Volibris consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Volibris drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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