(c)
2008 GlaxoSmithKline Inc. All Rights Reserved
(tm) VOLIBRIS used under license by GlaxoSmithKline Inc.
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 6 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 12 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY 13 STORAGE AND STABILITY 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 16
PHARMACEUTICAL INFORMATION 17 CLINICAL TRIALS 18 DETAILED PHARMACOLOGY 24 TOXICOLOGY 25 REFERENCES 26
ambrisentan
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet, 5 mg and 10 mg | Lactose (see DOSAGE FORMS, COMPOSITION AND PACKAGING) |
VOLIBRIS(tm) (ambrisentan) is indicated for: treatment of idiopathic ('primary') pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease in patients with WHO functional class II or III symptoms who have not responded to conventional therapy.
Patients with a known or suspected hypersensitivity to VOLIBRIS(tm) or any of its components (see DOSAGE FORMS, COMPOSITION AND PACKAGING). Pregnancy (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women)
General
There have been no studies to investigate the effect of VOLIBRIS(tm) on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.
Hematologic
The development of drug-related decreases in hemoglobin concentration and hematocrit has been associated with administration of endothelin receptor antagonists and was observed in clinical studies with VOLIBRIS(tm) and there have been cases where this has resulted in anemia (see ADVERSE REACTIONS). These decreases were generally observed within the first few weeks of treatment with VOLIBRIS(tm), and stabilized thereafter. Initiation of VOLIBRIS(tm) is not recommended for patients with clinically significant anemia (see Monitoring and Laboratory Tests).
Hepatic/Biliary/Pancreatic
Liver function abnormalities have been associated with pulmonary arterial hypertension. Hepatic enzyme elevations potentially related to therapy have been observed with endothelin receptor antagonists (ERAs). Therefore, hepatic function should be evaluated prior to initiation of VOLIBRIS(tm). If aminotransferase (alanine aminotransferase, ALT or aspartate aminotransferase, AST) concentrations are greater than 3 times upper limit of normal (> 3x ULN), initiation of VOLIBRIS(tm) is not recommended. Although the incidence of aminotransferase abnormalities was low, the possibility of serum aminotransferase elevations associated with VOLIBRIS(tm) administration cannot be excluded. Therefore monthly monitoring of ALT and AST is recommended (see Monitoring and Laboratory Tests; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).
Fluid Retention
Peripheral edema has been observed with ERAs including VOLIBRIS(tm). Peripheral edema may also be a clinical consequence of PAH. VOLIBRIS(tm) induced a dose- dependent increase of occurrence of mild to moderate peripheral edema, although in elderly patients the severity and frequency were higher (see ADVERSE REACTIONS). Fluid retention has been reported occurring within weeks after starting ambrisentan and, in some cases, has required intervention with a diuretic or hospitalization for fluid management. If clinically significant peripheral edema develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy.
Renal
VOLIBRIS(tm) has not been studied in individuals with renal impairment. Ambrisentan does not undergo significant renal metabolism or renal clearance (excretion), and therefore dose adjustment is unlikely to be required in patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Sexual Function/Reproduction
There are no pre-clinical or clinical data suggesting any significant change in female fertility, although women should avoid pregnancy while taking VOLIBRIS(tm) (see CONTRAINDICATIONS, Pregnancy). The development of testicular tubular atrophy that was not reversible after 13 or 20 weeks has been observed in male rats at dose levels of 10 to 300 mg/kg/day, although reduced fertility and morphologic effects on sperm only occurred at 300 mg/kg/day and were reversible. The effect on male human fertility is not known (see CLINICAL TRIALS and TOXICOLOGY).
Special Populations
The use of VOLIBRIS(tm) is contraindicated in pregnant women. Animal studies have reported increased incidences of fetal malformations and abnormalities following administration of ERAs including ambrisentan during pregnancy.
Women of child bearing potential should be advised of the risk of fetal harm if VOLIBRIS(tm) is taken during pregnancy. Pregnancy must be excluded before the start of treatment with VOLIBRIS(tm) and prevented thereafter by reliable contraception. Pregnancy tests during treatment with ambrisentan are recommended as clinically indicated. Women of child bearing potential should be advised to contact their physician immediately if they become pregnant or suspect they may be pregnant. If pregnancy is to be continued, VOLIBRIS(tm) should be discontinued and alternative treatment should be initiated (see CONTRAINDICATIONS and TOXICOLOGY, Pregnancy).
It is not known whether ambrisentan is excreted in human or animal milk. VOLIBRIS(tm) is not recommended for use by nursing mothers.
: There are no data available on the use of VOLIBRIS(tm) in patients under 18 years of age, and therefore its use in this age group is not recommended.
: No dose adjustment is required (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Monitoring and Laboratory Tests
VOLIBRIS(tm) has been associated with reductions in hemoglobin concentrations and hematocrit (see ADVERSE REACTIONS). Initiation of VOLIBRIS(tm) is not recommended for patients with clinically significant anemia. It is recommended that hemoglobin and/or hematocrit levels are measured prior to the initiation of VOLIBRIS(tm), again at one month, and periodically thereafter as clinically indicated. If a clinically significant decrease in hemoglobin or hematocrit is observed, and other causes have been excluded, dose reduction or discontinuation of treatment should be considered.
Liver transaminase levels should be measured prior to initiation of treatment and subsequently at monthly intervals. If patients develop sustained unexplained significant elevations of transaminases accompanied by signs or symptoms of hepatic injury (such as nausea, vomiting, fever, abdominal pain, jaundice or unusual lethargy or fatigue) or increases in bilirubin 2xULN, treatment with VOLIBRIS(tm) should be stopped. In patients without clinical symptoms of hepatic injury or jaundice, re-initiation of VOLIBRIS(tm) may be considered following resolution of hepatic enzyme abnormalities.
Adverse Drug Reaction Overview
The safety of VOLIBRIS(tm) has been evaluated in Phase II and Phase III clinical studies totalling 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily, ranging in exposure from 1 day to 3.5 years. Overall, VOLIBRIS(tm) was well tolerated. In placebo-controlled 12-week studies, the most commonly reported adverse drug reactions (ADRs) with VOLIBRIS(tm) were peripheral edema, headache, nasal congestion, sinusitis and palpitations. The adverse events reported during long-term therapy with VOLIBRIS(tm) were consistent with those observed in the 12-week, placebo-controlled studies. The incidence of adverse events was generally greater during the first 12 weeks of therapy. In placebo-controlled phase III studies, the proportion of subjects who prematurely discontinued for any reason was higher in the placebo group (15.9%) than in the combined VOLIBRIS(tm) group (7.6%). The proportion of subjects who discontinued because of adverse events was similar across all treatment groups: 3.0% in the placebo group and 2.3% in the combined VOLIBRIS(tm) group. In the combined placebo-controlled studies, six (4.5%) subjects in the placebo group died and 4 (1.5 %) subjects in the ambrisentan groups died. A higher proportion of subjects in the placebo group had at least 1 non-fatal SAE compared to the combined VOLIBRIS(tm) group. The most frequent SAEs for both the placebo and combined ambrisentan groups were right ventricular failure (placebo, 6.1%; ambrisentan, 1.9%) and (worsening) pulmonary hypertension (placebo, 3.8 %; ambrisentan, 1.1 %). Treatment-related SAEs occurred with a similar frequency across all ambrisentan treatment groups.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The following safety data for VOLIBRIS(tm) were obtained from two Phase III 12-week placebo controlled studies in subjects with PAH (ARIES-1 and ARIES-2). A total of 261 patients received VOLIBRIS(tm) at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. Table 1 presents adverse events with a >3% incidence in the combined ambrisentan treatment group and that were more frequent than placebo from the combined analysis of ARIES-1 and ARIES-2. AEs are summarized by randomized treatment assignment.
Table 1 Adverse Events in > 3% of PAH Patients Receiving VOLIBRIS(tm) and More Frequent than Placebo (ARIES-1 and ARIES-2, Population: Safety)
| Treatment group, n (%) Preferred Term | Placebo (N=132) | 5 mg Ambrisentan (N=130) | 10 mg Ambrisentan (N=67) | Combined Ambrisentan * (N=261) |
| Peripheral edema | 14 (10.6) | 24 (18.5) | 19 (28.4) | 45 (17.2) |
| Headache | 18 (13.6) | 20 (15.4) | 13 (19.4) | 38 (14.6) |
| Nasal congestion | 2 (1.5) | 7 (5.4) | 7 (10.4) | 15 (5.7) |
| Palpitations | 3 (2.3) | 5 (3.8) | 3 (4.5) | 12 (4.6) |
| Dyspnea | 4 (3.0) | 7 (5.4) | 3 (4.5) | 11 (4.2) |
| Constipation | 2 (1.5) | 4 (3.1) | 4 (6.0) | 10 (3.8) |
| Flushing | 1 (0.8) | 5 (3.8) | 1 (1.5) | 10 (3.8) |
| Nasopharyngitis | 1 (0.8) | 7 (5.4) | 2 (3.0) | 9 (3.4) |
| Abdominal pain | 1 (0.8) | 4 (3.1) | 2 (3.0) | 8 (3.1) |
| Sinusitis | 0 | 4 (3.1) | 3 (4.5) | 8 (3.1) |
Note: This table includes all adverse events >3% incidence in combined ambrisentan treatment group and more frequent than in the
placebo group, with a difference of >= 1% between the ambrisentan and placebo groups.
* Combined ambrisentan treatment group includes 2.5 mg dose group.
Adverse drug reactions were generally mild to moderate. The higher dose (10 mg) is associated with a higher incidence of peripheral edema, headache, nasal congestion, palpitations, constipation and sinusitis. Peripheral edema was the most common adverse event observed with VOLIBRIS(tm). All adverse events >1% and <= 3% incidence in the combined ambrisentan treatment group and more frequent than in the placebo group in Phase III clinical studies are as follows:
Blood and lymphatic disorders:
anemia
Cardiac disorders:
angina pectoris, tachycardia
Gastrointestinal disorders:
diarrhea, gastritis, abdominal pain - upper
General disorders and administration site conditions:
chest discomfort, chest pain, edema, non-cardiac chest pain, pyrexia
Infections and Infestations: Injury, poisoning, and procedural complications: Investigations:
pharyngitis, influenza, pneumonia
contusion
hemoglobin decreased
Metabolism and nutritional disorders:
anorexia, fluid retention, hypokalemia
Musculoskeletal and connective tissue disorders:
muscle cramp, myalgia
Psychiatric disorders:
insomnia, sleep disorder
Renal and Urinary tract disorders:
nocturia
Reproductive system and breast disorders:
vaginal hemorrhage
Respiratory, thoracic and mediastinal disorders:
lung crackles, pleural effusion, rhinitis, wheezing
Skin and subcutaneous tissue disorder:
pruritus, skin ulcer
Miscellaneous
: a number of patients (19%) showed an increase of gGT (> 3xULN). The clinical significance is not known.
The common adverse events observed during long-term treatment with VOLIBRIS(tm) were similar to those reported during the 12 week placebo-controlled periods. During long-term studies, commonly reported events (>= 10%) in the combined VOLIBRIS(tm) group - peripheral edema, headache, upper respiratory tract infection, dizziness, cough, arthralgia, right ventricular failure, pulmonary hypertension, dyspnea exacerbated, palpitations, diarrhea, nausea, nasopharyngitis, nasal congestion and anemia - were generally reported at a higher frequency in the 10 mg group.
Immune System Disorders: Hypersensitivity
Events suggestive of hypersensitivity to ambrisentan including descriptions of rash and angioedema have been reported uncommonly.
Abnormal Hematologic and Clinical Chemistry Findings
Hematologic Changes
In the placebo-controlled Phase III studies in patients with PAH, a decrease from baseline in mean hemoglobin (-0.84 g/dL) and hematocrit (-3% units) was observed in patients receiving VOLIBRIS(tm). Marked decreases in hemoglobin (> 15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of patients receiving VOLIBRIS(tm) and 4% of patients receiving placebo. Similar decreases in hemoglobin/hematocrit have been observed with other ERAs; the cause of the decrease is not fully understood, but it is not due to hemorrhage or hemolysis. The mean decrease was slightly greater with 10 mg (1.1 g/dL) than with 5 mg VOLIBRIS(tm) (0.76 g/dL). There were few events related to anemia, low hemoglobin or low hematocrit (n=8). These events appeared to be more frequent with 10 mg VOLIBRIS(tm) than lower doses or placebo.
Post-Marketing Adverse Drug Reactions
Post-marketing reports of fluid retention have been reported occurring within weeks after starting ambrisentan and in some cases, have required intervention with a diuretic or hospitalization for fluid management.
Overview
Studies with human liver tissue indicate that ambrisentan is metabolized by uridine 5'- diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S, CYP3A4 and CYP2C19. In vitro studies suggest that ambrisentan is a substrate of Organic Anion Transport Protein (OATP). In vitro studies show ambrisentan is a substrate but not an inhibitor of P-gp. The drug interaction potential of ambrisentan is not well characterized because in vivo drug interaction studies were not conducted with the following types of drugs: strong inhibitors of CYP2C19 (omeprazole), strong inducers of CYP3A and 2C19 (rifampin), strong inhibitors of the transporters P-gp (cyclosporine A) and OATP (cyclosporine A, rifampin); and inducers of CYPs, UGTs and P-gp (rifampin). The impact of co- administration of such drugs on ambrisentan exposure is therefore unknown. Regarding inhibition of CYP3A4, the only data available were obtained with ketoconazole (see Drug-Drug Interactions - Ketoconazole).
Drug-Drug Interactions
: Cyclosporine A is known to inhibit P-gp, Organic Anion Transport Protein and CYP3A4 which in vitro studies indicate ambrisentan is a substrate. Since drug-drug interaction studies with cyclosporine A have not been completed, caution is advised when VOLIBRIS(tm) is co-administered with cyclosporine A.
: Caution is advised when VOLIBRIS(tm) is co- administered with inducers of P-gp, CYPs, and UGTs. The impact of co-administration of such drugs on ambrisentan exposure is unknown.
VOLIBRIS(tm) is contraindicated in pregnancy. Drug-drug interaction studies with oral contraceptives and ambrisentan have not been completed, and therefore the effect of ambrisentan on oral contraceptives is not known.
: in healthy volunteers receiving a single dose of sildenafil (20 mg), daily doses of VOLIBRIS(tm) (10 mg) did not have a clinically relevant effect on the pharmacokinetics of sildenafil or the active metabolite, n-desmethyl sildenafil. Similarly, daily doses of sildenafil (20 mg tid) did not have a clinically relevant effect on the pharmacokinetics of a single dose of VOLIBRIS(tm) (10 mg) (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). Nonetheless, co-administration of the two drugs could result in a drop of blood pressure. The combination should therefore be used with caution.
Ketoconazole: data indicate that steady state administration of ketoconazole increases the AUC[?] and Cmax of ambrisentan by 35 and 20%, respectively. The clinical significance of these changes is not known. Patients on 10 mg of ambrisentan while on ketoconazole should be monitored closely for any signs of adverse effects.
In clinical studies of patients with PAH, co-administration of ambrisentan and omeprazole (an inhibitor of CYP2C19) did not significantly affect the pharmacokinetics of ambrisentan.
: in healthy volunteers receiving warfarin, daily doses of VOLIBRIS(tm)
(10 mg) did not have a clinically relevant effect on prothrombin time (PT), International Normalized Ratio (INR), or the pharmacokinetics of S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate). In patients with PAH receiving warfarin-type anticoagulants, concomitant administration of VOLIBRIS(tm) did not result in a clinically relevant change in PT, INR or anticoagulant dose (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Drug-Food Interactions
VOLIBRIS(tm) can be taken with or without food (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Drug-Herb Interactions
Interactions with herbal products have not been established.
Dosing Considerations
Treatment should only be initiated by a physician experienced in the treatment of PAH. VOLIBRIS(tm) treatment should only be initiated in women of childbearing potential following a negative pregnancy test and providing they are using a reliable method of contraception (see CONTRADINDICATIONS; WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women). VOLIBRIS(tm) is not recommended in patients with severe hepatic impairment and should be used with caution in patients with moderate hepatic impairment (see WARNINGS AND PRECAUTIONS; ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics and Special Populations and Conditions, Hepatic Insufficiency).
Recommended Dose and Dosage Adjustment
VOLIBRIS(tm) should be initiated at a dose of 5 mg once daily. Additional benefit may be obtained by increasing the dose to 10 mg once daily. Patients with PAH associated with connective tissue disease may require 10 mg VOLIBRIS(tm) for optimal efficacy. Consider increasing the dose to 10 mg VOLIBRIS(tm) providing the 5 mg dose is well tolerated (see ADVERSE REACTIONS). The maximum recommended daily dose is 10 mg. VOLIBRIS(tm) can be administered with or without food.
Missed Dose
If a dose of VOLIBRIS(tm) is missed, the patient should be advised to take it as soon as they remember, and then continue with the next dose at the regular interval. Two doses should not be taken at the same time to make up for a missed dose.
There is currently no experience with overdosage of VOLIBRIS(tm). No specific antidote is available. In healthy volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Due to the mechanism of action of ambrisentan, an overdosage of VOLIBRIS(tm) could potentially result in hypotension. In the case of pronounced hypotension, active cardiovascular support may be required. For management of a suspected drug overdose, contact your regional Poison Control Centre
Mechanism of Action
Ambrisentan is an orally active, propanoic acid-class, endothelin receptor antagonist (ERA) that is selective for the endothelin type A (ETA) receptor. Selective inhibition of the ETA receptor inhibits phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation, while preserving nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance that is associated with the endothelin type B (ETB) receptor.
Pharmacodynamics
Invasive hemodynamic parameters were assessed in patients with pulmonary arterial hypertension (PAH) at baseline and after 12 weeks (n=29) in a Phase II study. Treatment with ambrisentan resulted in a significant increase in mean cardiac index (+0.3 L/min/m2; 95% CI: 0.15 to 0.51; p < 0.001), and a decrease in mean pulmonary artery pressure (-5.2 mmHg; 95% CI: -7.6 to -2.9; p < 0.001), and mean pulmonary vascular resistance (-2.8 mmHg/L/min; 95% CI: -3.8 to -1.8; p < 0.001) for the combined ambrisentan group. There was also a trend toward a reduction in mean right atrial pressure (-0.5 mmHg).
In patients with PAH, reductions in B-type natriuretic peptide (BNP) have been shown to parallel improvements in hemodynamics and 6-minute walk distance. Combined analysis of results from two Phase III placebo-controlled studies demonstrated that plasma concentrations of BNP decreased in patients who received ambrisentan for 12 weeks. The geometric mean plasma concentration of BNP increased by 11% in the placebo group, and decreased by 29% in the 2.5 mg, 30% in the 5 mg, and 45% in the 10 mg group (p < 0.001 for each dose group). A positive association was observed between change in BNP and improvement in WHO class at Week 12.
In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either VOLIBRIS(tm) 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(tm) 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of VOLIBRIS(tm) increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving VOLIBRIS(tm) 5-10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.
Pharmacokinetics
Absorption: Ambrisentan is absorbed rapidly in humans. The absolute bioavailability of ambrisentan is not known. After oral administration, maximum plasma concentrations (Cmax) of ambrisentan typically occurs between 1 and 2 hours post dose under both fasted and fed conditions. Cmax and area under the plasma concentration-time curve (AUC) increase dose proportionally over the therapeutic dose range. Steady-state is generally achieved following 4 days of repeat dosing. A food-effect study involving administration of ambrisentan to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased 12% while the AUC remained unchanged. This decrease in peak concentration is not clinically significant, and therefore ambrisentan can be taken with or without food. Distribution: Ambrisentan is highly plasma protein bound. The in vitro plasma protein binding of ambrisentan was, on average, 99% and independent of concentration over the range of 0.2 - 20 microgram/mL. Ambrisentan is primarily bound to albumin (96.5%) and to a lesser extent to alpha1-acid glycoprotein. The distribution of ambrisentan into red blood cells is low, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively.
Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S, and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%). The binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less than ambrisentan. Therefore at concentrations observed in the plasma (approximately 20% relative to parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological activity of ambrisentan.
Using human liver microsome, in vitro data have shown that at therapeutic concentrations, ambrisentan does not inhibit UGT1A1, UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4. Additional in vitro studies showed that ambrisentan is a substrate for the organic anion export pump (OATP); the interaction between strong inhibitors of this transporter and ambrisentan is possible (see DRUG INTERACTIONS). Furthermore, ambrisentan does not affect biliary/xenobiotic transporters NTCP, OATP, multi-drug resistance protein isoform-2 (MRP2), P-glycoprotein (P-gp), or BSEP.
Ambrisentan and its metabolites are primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. The half-life after multiple dosing is approximately 15 hours (range 13.6 to
16.5 hours) in healthy volunteers and 9 to 15 hours in PAH patients. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively.
Special Populations and Conditions
There are no data available on the use of ambrisentan in patients under 18 years of age.
Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with PAH, the pharmacokinetics of ambrisentan were not significantly influenced by age (see DOSAGE AND ADMINISTRATION).
Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with PAH, the pharmacokinetics of ambrisentan were not significantly influenced by gender.
Hepatic Insufficiency: The pharmacokinetics of ambrisentan in patients with severe hepatic impairment or with clinically significant elevated hepatic transaminases has not been studied. However, since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile, moderate to severe hepatic impairment would be expected to increase exposure (Cmax and AUC) of ambrisentan, however the magnitude of this and any effect on safety and efficacy has not been evaluated. Therefore ambrisentan should be used with caution in patients with moderate to severe hepatic impairment (see WARNINGS AND PRECAUTIONS, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
No pharmacokinetic studies have been conducted in renally impaired patients. However, the renal excretion of ambrisentan is minimal, therefore renal impairment should not significantly increase exposure to ambrisentan.
Store between 15-30degC.
VOLIBRIS(tm) (ambrisentan) 5 mg film-coated tablets are square, pale pink tablets engraved with 'GS' on one side and 'K2C' on the other. VOLIBRIS(tm) (ambrisentan) 10 mg film-coated tablets are oval, deep pink tablets engraved with 'GS' on one side and 'KE3' on the other. Each film-coated tablet contains the following non-medicinal ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, titanium dioxide and macrogol/polyethylene glycol 3350, lecithin and FD&C Red #40 Aluminium Lake. VOLIBRIS(tm) tablets are available in blister packs of 30 tablets.
PART II: SCIENTIFIC INFORMATION
Proper name: ambrisentan Chemical name: (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3- diphenylpropanoic acid Molecular formula and molecular mass: C22H22N2O4, 378.42 Structural formula:
CH3
H3CO N
O
N
CH3 Physicochemical properties: 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.
Table 2 Summary of the Design and Patient Demographics in the Two Pivotal Clinical Trials of VOLIBRIS(tm) (ambrisentan) Tablets in Patients with Pulmonary Arterial Hypertension (PAH)
| Study Code | Trial design | Dosage, route of administration and duration | Study subjects (n=number) | Mean age (range) | Gender |
| ARIES-1 | Phase III, randomized, | 5 mg and 10 mg | Placebo: n=67 | 50.1 | Male: 33 |
| double-blind, placebo- | tablets taken orally | 5 mg: n=67 | (17-82) | (16.4%) | |
| controlled, | qd for 12 weeks | 10 mg: n=67 | Female: 168 | ||
| multicentre, | (83.6%) | ||||
| multinational | |||||
| ARIES-2 | Phase III, randomized, | 2.5 mg and 5 mg | Placebo: n=65 | 50.9 | Male: 49 |
| double-blind, placebo- | tablets taken orally | 2.5 mg: n=64 | (20-81) | (25.5%) | |
| controlled, | qd for 12 weeks | 5 mg: n=63 | Female: 143 | ||
| multicentre, | (74.5%) | ||||
| multinational |
Two randomised, double-blind, multi-centre, placebo controlled, Phase III pivotal studies were conducted (ARIES-1 and ARIES-2). ARIES-1 included 201 patients and compared VOLIBRIS(tm) (ambrisentan) 5 mg and 10 mg with placebo. ARIES-2 included 192 patients and compared VOLIBRIS(tm) 2.5 mg and 5 mg with placebo. In both studies, VOLIBRIS(tm) was added to patients' supportive/background medication, which may have included a combination of digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium channel blockers, ACE inhibitors). The primary study endpoint was 6-minute walk distance (6MWD). In addition, clinical worsening, WHO functional class, dyspnea and SF-36(r) Health Survey were assessed. Patients enrolled had WHO functional class I-IV PAH resulting from idiopathic PAH (IPAH) (64%) or non-IPAH associated with connective tissue disease (32%), anorexigen use (1%) or HIV infection (3%). The majority of patients had WHO functional Class II (38.4%) or Class III (55.0%) symptoms. Patients completing the ARIES 1 and 2 studies were able to continue treatment with VOLIBRIS(tm) in an extension study (ARIES-E). A total of 483 subjects with PAH have received VOLIBRIS(tm) in Phase II or Phase III clinical studies, with a mean exposure of 79.5 +- 50.28 weeks (1.5 years) and a maximum exposure of 212.3 weeks (4.1 years). Of these, 343 (71.0%) subjects have had drug exposures of at least 1 year, and 120 (24.8%) subjects have had drug exposures of 2 or more years.
The primary endpoint defined for these studies was improvement in exercise capacity assessed by change from baseline in 6MWD at 12 weeks. In both studies, treatment with VOLIBRIS(tm) resulted in a significant improvement in 6MWD for each dose of VOLIBRIS(tm). The improvement in exercise capacity was evident after 4 weeks of treatment and was maintained at week 12 of the double-blind treatments. The placebo-adjusted improvement in mean 6MWD at week 12 compared to baseline was 30.6 m (95% CI: 2.9 to 58.3; p=0.008) and 59.4 m (95% CI: 29.6 to 89.3; p <0.001) for the 5 mg group, in ARIES 1 and 2, respectively. The placebo-adjusted improvement in mean 6MWD at week 12 in patients in the 10 mg group in ARIES-1 was 51.4 m (95% CI: 26.6 to 76.2; p <0.001). Results of the 6MWD at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 3 and Figure 1.
Table 3 Changes from Baseline in 6-minute Walk Distance (meters) at Week 12 in Phase III studies
| 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) | |
| Baseline | 341.9 +- 73.47 | 339.6 +- 76.68 | 341.5 +- 7.288 | 342.7 +- 85.93 | 347.3 +- 83.81 | 355.3 +- 84.45 |
| Mean change from baseline | -7.8 +- 78.88 | 22.8 +- 82.98 | 43.6 +- 65.91 | -10.1 +- 93.79 | 22.2 +- 83.67 | 49.4 +- 75.36 |
| Placebo adjusted mean change from baseline | 30.6 | 51.4 | 32.3 | 59.4 | ||
| p-value + | 0.008 | <0.001 | 0.022 | <0.001 | ||
Mean +- standard deviation
+ p-values are Wilcoxon rank sum test comparisons of VOLIBRIS(tm) to placebo at Week 12 stratified by idiopathic PAH and non-idiopathic PAH patients
0 Placebo
5 5 mg
10 mg
-15
Baseline Week 4 Week 8 Week 12
0 Placebo
5 2.5 mg
5 mg
-15
Baseline Week 4 Week 8 Week 12
| ARIES-1 |
| Meters |
| ARIES-2 |
| Meters |
Mean change from baseline in 6-minute walk distance in the placebo and VOLIBRIS(tm) groups Values are expressed as mean +- standard error of mean.
Results from the extension studies also indicated that the benefits were maintained at 48 weeks. The mean change in 6MWD from baseline at week 48 was +35.2 m (95% CI: 13.0 to 57.5; n=68) for the 5 mg dose, and +30.2 m (95% CI: 10.8 to 49.6; n=32) for the 10 mg dose. Symptoms of PAH were assessed using Borg Dyspnea Index (BDI), WHO functional class and SF-36(r) Health Survey physical functioning scale. Treatment with VOLIBRIS(tm) led to statistically significant improvements in BDI at week 12 (Table 4). Improvements in the physical functioning scale (SF-36(r)) were also observed, however, were not statistically significant.
Table 4 Summary of Secondary Endpoints from Study ARIES-1 and ARIES-2 at 12 Weeks (Population ITT)
| ARIES-1 | ARIES-2 | ||||||
| Placebo | Ambrisentan 5 mg | Ambrisentan 10 mg | Placebo | Ambrisentan 2.5 mg | Ambrisentan 5 mg | ||
| Change in | Change from | 0.0 | -0.3 | -0.9 | 0.8 | -0.2 | -0.4 |
| Borg | baseline to | (-0.55, 0.54) | (-0.79, 0.16) | (-1.3, -0.41) | (0.17, 0.54) | (-0.74, 0.34) | (-0.87, 0.14) |
| Dyspnea | Week 12 | ||||||
| Index | Comparison | -0.3 | -0.9 | -1.0 | -1.2 | ||
| (BDI) | vs placebo, | (-1.0, 0.4) | (-1.6, -0.2) | (-1.9, -0.2) | (-2.0, -0.4) | ||
| point estimate | p=0.316 | p=0.002 | p=0.046 | p=0.040 | |||
| (95% CI) | - | + | + | + | |||
| Change in WHO Class, N (%) | Improved | 16 (23.9%) | 19 (28.4%) | 20 (29.9%) | 11 (16.9%) | 10 (15.6%) | 9 (14.3%) |
| Deteriorated | 11 (16.4%) | 1 (1.5%) | 3 (4.5%) | 12 (18.5%) | 3 (4.7%) | 2 (3.2%) | |
| Comparison | p=0.0726 | p=0.0957 | p= 0.2058 | p=0.1872 | |||
| with placebo 1 | - | - | - | - | |||
| Change in SF-36 Physical component summary | Change from baseline, Mean (SD) | 1.82 (9.25) | 1.88 (8.68) | 4.79 (7.90) | -0.15 (7.29) | 3.78 (7.63) | 2.97 (7.79) |
| Comparison | p=0.992 | p=0.056 | 0.005 | 0.052 | |||
| with placebo | - | - | + | - | |||
Based on analysis of 7-point change from baseline scale
+ statistically significant result, - not statistically significant
VOLIBRIS(tm) significantly delayed clinical worsening (the measure included a benefit for both death and hospitalization for PAH). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study discontinuation due to the addition of other PAH therapeutic agents, or study discontinuation due to 2 or more early escape criteria. At 12 weeks, the hazard ratios demonstrated a 71% reduction (95% CI: 41% to 86%) in the probability of clinical worsening at any time for patients receiving ambrisentan compared to placebo. This was supported by a significant log- rank test (p=0.003). In the ARIES studies, those patients with WHO functional class II symptoms at baseline had a mean BDI of 2.98, a mean 6MWD of 375 m; 47% had a 6MWD of more than 400 m. Those with WHO functional class III symptoms had a mean BDI of 4.38 and a mean 6MWD of 330 m at baseline. In patients with class II and class III symptoms, increases in mean 6MWD were observed with 5 mg and 10 mg VOLIBRIS(tm) compared to placebo after 12 weeks treatment (Table 5). Improvement in secondary endpoints also supported efficacy in both WHO functional class II and class III patients.
Table 5 Improvement in 6MWD at Week 12 in Phase III Studies in patients with WHO Functional Class II symptoms or WHO Functional Class III symptoms (Study ARIES-C, Population ITT)
| ARIES-1 | ARIES-2 | ||||||
| Placebo | VOLIBRIS(tm) 5 mg | VOLIBRIS(tm) 10 mg | Placebo | VOLIBRIS(tm) 2.5 mg | VOLIBRIS(tm) 5 mg | ||
| WHO | Change in | -0.3 | +26.6 | +43.4 | -7.3 | +37.0 | +61.4 |
| Class II | 6MWD from | (-19.3, 18.7) | (-1.0, 54.2) | (17.6, 69.2) | (-45.9, 31.4) | (9.1,64.9) | (31.3, 91.5) |
| baseline to Week | |||||||
| 12, mean (95% | |||||||
| CI) | |||||||
| Placebo-Adjusted | 27.0 | 43.7 | +44.2 | +68.6 | |||
| improvement in | (-4.8, 58.7) | (12.8, 74.7) | (-1.1, 89.6) | (21.5, 115.8) | |||
| 6MWD, mean | p=0.0460 | p=0.0072 | p=0.0624 | p=0.0104 | |||
| (95% CI) | |||||||
| WHO | Change in | -15.2 | +18.7 | +42.2 | -15.2 | +6.2 | +38.3 |
| Class III | 6MWD from | (-45.0, 14.5) | (-5.8, 43.3) | (21.0, 63.4) | (-48.3, 17.8) | (-26.2, 38.7) | (11.7, 64.9) |
| baseline to Week | |||||||
| 12, mean (95% | |||||||
| CI) | |||||||
| Placebo-Adjusted | +34.0 | +57.4 | 21.4 | 53.5 | |||
| improvement in | (-4.1, 72.1) | (20.5, 94.3) | (-24.8, 67.7) | (11.2, 95.8) | |||
| 6MWD, mean | p=0.0624 | p=0.0187 | p=0.4500 | p=0.0217 | |||
| (95% CI) | |||||||
Analyzing the change from baseline in 6MWD at week 12 by PAH etiology (IPAH versus non-IPAH) demonstrated significant improvements compared to placebo for all VOLIBRIS(tm) dose groups for the IPAH subgroup. The majority of the non-IPAH patients in the VOLIBRIS(tm) phase III studies (124/142; 87%) had PAH-CTD (specifically scleroderma spectrum of disease). Those patients treated with VOLIBRIS(tm) 10 mg showed a greater improvement in 6MWD compared with those treated with 5 mg (Table 6).
Table 6 Summary of 6-Minute Walk Distance Change from Baseline to Week 12 by PAH Stratification using LOCF (Population: ITT)
| ARIES-1 | ARIES-2 | ||||||
| Treatment Group | Placebo | VOLIBRIS 5 mg | VOLIBRIS 10 mg | Placebo | VOLIBRIS 2.5 mg | VOLIBRIS 5 mg | |
| IPAH | |||||||
| Change from baseline to Week 12 | N | 43 | 42 | 41 | 42 | 42 | 41 |
| Mean (SD) | -6.3 (82.14) | 36.6 (85.42) | 50.6 (58.22) | -20.6 (101.23) | 35.7 (67.97) | 55.1 (86.58) | |
| Comparison versus placebo | Point estimate | 42.9 | 56.9 | 56.3 | 75.7 | ||
| p-value 1 | 0.0053 | 0.0011 | 0.005 | <0.001 | |||
| Non-IPAH | |||||||
| Change from baseline to Week 12 | N | 24 | 25 | 26 | 23 | 22 | 22 |
| Mean (SD) | -10.6 (74.32) | -0.4 (74.69) | 32.4 (76.38) | 9.1 (76.77) | -3.5 (102.10) | 38.6 (47.96) | |
| Comparison versus placebo | Point estimate | 10.2 | 43.0 | -12.6 | 29.5 | ||
| p-value 1 | 0.4965 | 0.0487 | 1.000 | 0.170 | |||
Wilcoxon rank sum test stratified by IPAH and non-IPAH subjects
An assessment of survival for patients with idiopathic PAH showed that the 1 year survival of patients treated with VOLIBRIS(tm) was 96% (95 CI: 94, 99) compared with a predicted survival rate for untreated patients of 72% (NIH Registry). At 2 years expected estimated survival on ambrisentan was 87% (95% CI: 81, 94). The probability of not having a clinical worsening event (based on Kaplan-Meier estimates) in idiopathic PAH patients at 1 year was 85.6% (95% CI: 81, 90). Hepatic function was assessed in clinical studies. In ARIES 1 and 2, there were no cases of aminotransferase abnormalities > 3x the upper limit of normal (ULN) in 262 patients receiving VOLIBRIS(tm) compared with three cases (out of 132) in patients receiving placebo (2.3%). The cumulative incidence of serum aminotransferase abnormalities > 3xULN in all Phase II and III (including extension) studies was 3.5% (17 of 483 subjects over a mean exposure duration of 79.5 weeks). In an open label study (AMB222), VOLIBRIS(tm) was studied in 36 patients to evaluate the incidence of increased serum aminotransferase concentrations in patients who had previously discontinued other endothelin receptor antagonist (ERA) therapy due to aminotransferase abnormalities. None of the patients enrolled had a confirmed serum ALT > 3xULN during 54 weeks of VOLIBRIS(tm) therapy that required permanent discontinuation of treatment. No clinically meaningful effects on the pharmacokinetics of ambrisentan or sildenafil were seen during a drug-drug interaction study in healthy volunteers, and the combination was well tolerated. The number of patients who received concomitant VOLIBRIS(tm) and sildenafil was 22 patients (5.7%) and 17 patients (47%) in ARIES-E and AMB222, respectively. No additional safety concerns were identified in these patients. In ARIES-E (extension study), 21 patients (5.5%) required prostanoid therapy. Adverse events observed in patients receiving concomitant prostanoid and VOLIBRIS(tm) therapy were consistent with the severity of PAH in these patients.
Ambrisentan is a specific, competitive endothelin receptor antagonist, with ETA receptor selectivity. This pharmacologic property is the primary mode of action of ambrisentan. Pharmacological activity of ambrisentan has been evaluated in a series of assays and animal models. Primary Pharmacodynamics: In vitro studies using membrane preparations from human ventricular myocytes, showed that Ambrisentan is an endothelin antagonist with a Ki of 16 pM against ETA receptors. The selectivity of ambrisentan for ETA receptors over ETB receptors is about 4000-fold. The relative affinity of the R-enantiomer was markedly weaker as compared to the value for the S-enantiomer.
In vivo
studies have been performed in a rat model of endothelin-induced hypertension. Ambrisentan dose-dependently (1, 3, or 10 mg/kg p.o.) reduced the increases in arterial pressure resulting from endothelin (Big ET-1) infusion.
No studies were performed on the pharmacodynamic effects of Ambrisentan in animal models of pulmonary hypertension. Secondary Pharmacodynamics: When tested for specificity using a battery (100) of receptors and ion channels, ambrisentan at 10 mM was not active (< 50% inhibition). The R-enantiomer and 4-hydroxymethyl metabolite of ambrisentan were also inactive in a similar specificity panel. In normotensive rats, oral administration of 300 mg/kg of ambrisentan or intravenous administration of 100 mg/kg ambrisentan caused initial increases in arterial pressure and heart rate that were followed by sustained reductions in these cardiovascular parameters. In normotensive dogs, oral administration of 1, 10, and 100 mg/kg of ambrisentan caused dose-dependent reductions in arterial pressure that were not compensated for by increased heart rate.
Safety pharmacology studies were conducted to examine the effect of ambrisentan on the central and peripheral nervous system, cardiovascular and respiratory, gastrointestinal and renal systems, as well as cardiac conductivity (hERG cell current and guinea pig papillary muscle), uterine smooth muscle contractility, blood coagulation and spleen cell mitogenicity.
There was no evidence of overt central or peripheral effects in mice and rats after intravenous and oral administration of doses up to 100 mg/kg and 300 mg/kg, respectively. The results from these safety pharmacology tests indicate that high concentrations of ambrisentan produced little to no effects in in vitro, ex vivo and in whole animal models and suggests minimal risk for off-target biological effects; however, large single doses of ambrisentan could lower arterial pressure and have the potential for causing hypotension and symptoms related to vasodilation. In addition, in rats, ambrisentan (single i.v. or oral doses) reduced renal sodium, chloride and calcium excretion rates in a dose-dependent manner. No pharmacodynamic drug interaction studies were performed.
The principal findings in repeat dose toxicity studies in mice and rats with ambrisentan are in part attributed to exaggerated pharmacology and include effects in the nasal cavity and testes. Repeat dose studies in the dog reveal ambrisentan to be well tolerated with findings limited to fundic glandular atrophy and clinical signs of audible breathing and gastrointestinal disturbance. Deaths or findings resulting in early sacrifice of animals attributed to oral administration of ambrisentan occurred in repeat-dose toxicity studies in rats at >= 100 mg/kg/day and in dogs at 1500 mg/kg/day. An increased mortality rate also occurred in 2-year carcinogenicity studies in rats at 30/20 mg/kg/day and 60/40 mg/kg/day (initial daily dose of 30 mg/kg/day subsequently lowered to 20 mg/kg/day, and 60 mg/kg/day subsequently lowered to 40 mg/kg/day) and mice at 250/150 mg/kg/day (initial daily dose of 250 mg/kg/day subsequently lowered to 150 mg/kg/day). Inflammation and changes in the nasal cavity epithelium and/or turbinates has been seen with chronic administration of ambrisentan and other endothelin receptor antagonists (ERAs) to rodents and, to a lesser extent, dogs. Carcinogenesis and Mutagenesis: The genotoxicity of ambrisentan was assessed in a comprehensive battery of in vitro and in vivo studies. Ambrisentan was clastogenic in human lymphocytes in vitro both in the presence and absence of metabolic activation. Ambrisentan was not mutagenic to Salmonella typhimurium, did not elicit unscheduled DNA synthesis in rat liver, and was not clastogenic in an in vivo micronucleus study conducted in male rats. There were no treatment-related increases in the incidence of tumours in 2 year oral studies in rats and mice.
The development of testicular tubular atrophy and sterility has been linked to the chronic administration of ERAs to rodents. Testicular tubular atrophy was observed at all dose levels (10 to 300 mg/kg/day) in oral fertility studies with male rats that was not reversible after 13 or 20 weeks following cessation of dosing. Reduced fertility and morphologic effects on sperm only occurred at 300 mg/kg/day and were reversible. No effects on sperm count or sperm motility were observed. Testicular tubular atrophy (focal/multifocal or diffuse) was also observed in repeat dose studies in rats and mice. There were no significant effects on fertility or embryofetal development in female rats dosed up to the time of implantation.
Teratogenicity is a class effect of ERAs. The effect of ambrisentan on embryo-fetal development has been assessed in rats and rabbits after oral dose administration on gestation days 6-17 and 6-18, respectively. In both species, abnormalities of the lower jaw, tongue, and/or palate were consistently observed at all dose levels. Additionally, interventricular septal defects, trunk vessel defects, thyroid and thymus abnormalities, ossification of the basisphenoid bone, and an increased incidence of left umbilical artery were observed in the rat study and heart and associated blood vessel abnormalities were seen in the rabbit study.
1. Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46(3):529-535.
PART III: CONSUMER INFORMATION
Pr
VOLIBRIS(tm)
ambrisentan
5 mg and 10 mg film-coated tablets
This leaflet is part III of a three-part "Product Monograph" published when VOLIBRIS(tm) (ambrisentan) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about VOLIBRIS(tm). Contact your doctor or pharmacist if you have any questions about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
VOLIBRIS(tm) is used to treat idiopathic ('primary') pulmonary arterial hypertension (PAH) and pulmonary arterial
hypertension associated with connective tissue disease, which is high blood pressure in the blood vessels between the heart
and the lungs.
What it does:
VOLIBRIS(tm) reduces high blood pressure by relaxing these
blood vessels. VOLIBRIS(tm) belongs to the class of medicines known as endothelin receptor antagonists (ERA).
Tests your doctor will do before treatment:
a blood test to check that your liver is working properly and to check for anemia (reduction in red blood cells);
a pregnancy test.
When it should not be used:
Do not take VOLIBRIS(tm) if:
you are allergic to ambrisentan or any other ingredients in the tablet (see What the important nonmedicinal ingredients are);
you are pregnant, are planning to become pregnant, or could get pregnant because you are not using reliable birth control (contraception) (see WARNINGS AND PRECAUTIONS).
What the medicinal ingredient is:
ambrisentan
What the important nonmedicinal ingredients are:
Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide and macrogol/polyethylene glycol 3350, lecithin and FD&C Red #40 Aluminium Lake.
What dosage forms it comes in:
5 mg and 10 mg film-coated tablets
WARNINGS AND PRECAUTIONS
Warnings and Precautions
Before you use VOLIBRIS(tm) talk to your doctor or pharmacist if you:
are pregnant or thinking of becoming pregnant;
could become pregnant because you are not using reliable birth control (contraceptive) methods;
are breastfeeding
BEFORE you use VOLIBRIS(tm) talk to your doctor or pharmacist if:
you have or ever had liver problems
you have a low number of red blood cells (anemia)
Tests during treatment:
Some patients taking VOLIBRIS(tm) were found to have abnormal liver function (increase in liver enzymes) and some
patients developed anemia (reduction in red blood cells). Because these findings may not cause symptoms you can feel
or observe yourself, your doctor will do regular blood tests to
check for any changes in your liver function and for anemia.
Liver function:
This blood test will be done every month or more frequently, if needed.
If you develop abnormal liver function, your doctor may decide to stop treatment with VOLIBRIS(tm). When your blood test results for liver function return to normal, your doctor may decide to restart treatment with VOLIBRIS(tm).
Anemia:
This blood test will be done after 1 month and periodically after that.
If you develop anemia, your doctor may decide to perform further tests to investigate the cause.
INTERACTIONS WITH THIS MEDICATION
Tell your doctor or pharmacist if you're taking any other medicines or when you start taking new ones - these include herbal medicines or other medicines you bought without a prescription.
PROPER USE OF THIS MEDICATION
Usual dose:
The usual dose of VOLIBRIS(tm) is 5 mg, once a day. Your doctor may decide to increase your dose to 10 mg, once a day.
You can take VOLIBRIS(tm) with or without food.
| SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM | ||||
| Symptom / effect | Talk with your doctor or pharmacist | Stop taking drug and call your doctor or pharmacist | ||
| Only if severe | In all cases | |||
| Very Common | Swelling (edema), especially in the ankles and feet | 9 | ||
| Headache | 9 | |||
| Common | Low number of red blood cells (anemia), which can cause tiredness, weakness, shortness of breath and feeling generally unwell | 9 | ||
| Flushing (redness of the skin) | 9 | |||
| A runny or blocked nose, congestion or pain in the sinuses | 9 | |||
| Uncommon | Allergic reactions, rash or itching and swelling (usually of the face, lips, tongue or throat), which may cause difficulty in breathing or swallowing | 9 | ||
| Rare | yellowing of the skin or eyes (jaundice) or other symptoms such as nausea, vomiting, fever, abdominal pain or unusual tiredness | 9 | 9 | |
Overdose:
If you accidentally take too much, ask your doctor or pharmacist for advice.
For management of a suspected drug overdose, contact your regional Poison Control Centre
Missed Dose:
If you forget to take a dose of VOLIBRIS(tm), just take the tablet as soon as you remember, then continue with the next
dose at your usual time. Don't take two tablets at the same time to make up for a forgotten dose.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Like all medicines, VOLIBRIS(tm) can cause side effects. Your chances of getting these sides effects will depend on many things, including how much VOLIBRIS(tm) you take.
The following side effects have been frequently reported: peripheral (legs and arms) edema, headache, nasal congestion, (blocked nose), sinusitis and palpitations.
This is not a complete list of side effects. For any unexpected effects while taking VOLIBRIS(tm), contact your doctor or pharmacist.
HOW TO STORE IT
Store between 15-30degC.
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:
By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789
Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca
By regular mail:
Canada Vigilance National Office
Marketed Health Products Safety and Effectiveness Information Bureau
Marketed Health Products Directorate Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9
NOTE: Should you require information related to the management of side effects, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.
MORE INFORMATION
This document plus the full product monograph, prepared for health professionals can be found at:
http://www.gsk.ca or by contacting the sponsor, GlaxoSmithKline Inc.
7333 Mississauga Road Mississauga, Ontario
L5N 6L4
1-800-387-7374
This leaflet was prepared by GlaxoSmithKline Inc. Last revised: March 13, 2008
(c)
2008 GlaxoSmithKline Inc. All Rights Reserved
(tm) VOLIBRIS used under license by GlaxoSmithKline Inc.