|Description||Ipilimumab, a recombinant human monoclonal antibody (IgG1 kappa immunoglobin), is an antineoplastic agent developed by Bristol-Myers Squibb and Medarex for the treatment of unresectable or metastatic melanoma in adults. Ipilimumab received FDA approved on March 25, 2011. In October 2015, the FDA approved expanded the indications for Ipilimumab, allowing it to be used to reduce the risk of the deadly skin cancer returning after surgery.|
|Protein chemical formula||C6572H10126N1734O2080S40|
|Protein average weight||148000.0 Da|
>Ipilimumab heavy chain (patent appl. US20150283234)
>Ipilimumab light chain
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDownload FASTA Format
|External Identifiers ||Not Available|
|Approved Prescription Products|
|Name||Dosage||Strength||Route||Labeller||Marketing Start||Marketing End|
|Yervoy||Liquid||5 mg||Intravenous||Bristol Myers Squibb||2012-03-08||Not applicable||Canada|
|Yervoy||Injection||5 mg/mL||Intravenous||E.R. Squibb & Sons, L.L.C.||2011-03-25||Not applicable||US|
|Yervoy||Injection||5 mg/mL||Intravenous||E.R. Squibb & Sons, L.L.C.||2011-03-25||Not applicable||US|
|Approved Generic Prescription Products||Not Available|
|Approved Over the Counter Products||Not Available|
|Unapproved/Other Products ||Not Available|
|International Brands||Not Available|
|Brand mixtures||Not Available|
|Indication||Ipilimumab is indicated for the treatment of unresectable or metastatic melanoma in adults. It is also used to reduce the risk of the deadly skin cancer returning after surgery.|
|Structured Indications |
|Clinical Trials |
|0||Active Not Recruiting||Treatment||Melanoma||1|
|1||Active Not Recruiting||Treatment||Acute Lymphocytic Leukemia (ALL) / Chronic Lymphocytic Leukaemia (CLL) / Lymphoma, B Cell||1|
|1||Active Not Recruiting||Treatment||Advanced Tumor / Metastatic Tumors||1|
|1||Active Not Recruiting||Treatment||Castrate Resistant Prostate Cancer (CRPC) / Prostate Cancers||1|
|1||Active Not Recruiting||Treatment||Malignant Melanoma||1|
|1||Active Not Recruiting||Treatment||Melanoma||2|
|1||Active Not Recruiting||Treatment||Melanoma (Skin)||1|
|1||Active Not Recruiting||Treatment||Recurrent Melanoma / Stage IV Melanoma / Tumors Metastatic to Brain||1|
|1||Active Not Recruiting||Treatment||Unresectable Melanoma||1|
|1||Completed||Treatment||Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(15;17)(q22;q12) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative / Childhood Myelodysplastic Syndromes / Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Disseminated Neuroblastoma / Neoplasms, Malignant / Ovarian Choriocarcinoma / Ovarian Embryonal Carcinoma / Ovarian Immature Teratoma / Ovarian Mature Teratoma / Ovarian Mixed Germ Cell Tumor / Ovarian Monodermal and Highly Specialized Teratoma / Ovarian Polyembryoma / Ovarian Yolk Sac Tumor / Previously Treated Myelodysplastic Syndromes / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Adult Acute Myeloid Leukemia / Recurrent Adult Burkitt Lymphoma / Recurrent Adult Diffuse Large Cell Lymphoma / Recurrent Adult Diffuse Mixed Cell Lymphoma / Recurrent Adult Hodgkin's Lymphoma / Recurrent Adult Immunoblastic Large Cell Lymphoma / Recurrent Adult Lymphoblastic Lymphoma / Recurrent Grade 3 Follicular Lymphoma / Recurrent Malignant Testicular Germ Cell Tumor / Recurrent Mantle Cell Lymphoma / Recurrent Neuroblastoma / Recurrent Ovarian Epithelial Cancer / Recurrent Ovarian Germ Cell Tumor / Refractory Chronic Lymphocytic Leukemia / Refractory Multiple Myeloma / Relapsing Chronic Myelogenous Leukemia / Stage I Multiple Myeloma / Stage II Multiple Myeloma / Stage II Ovarian Epithelial Cancer / Stage III Malignant Testicular Germ Cell Tumor / Stage III Multiple Myeloma / Stage III Ovarian Epithelial Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer / Stage IV Ovarian Epithelial Cancer / Testicular Choriocarcinoma / Testicular Choriocarcinoma and Embryonal Carcinoma / Testicular Choriocarcinoma and Seminoma / Testicular Choriocarcinoma and Teratoma / Testicular Choriocarcinoma and Yolk Sac Tumor / Testicular Embryonal Carcinoma / Testicular Embryonal Carcinoma and Seminoma / Testicular Embryonal Carcinoma and Teratoma / Testicular Embryonal Carcinoma and Teratoma With Seminoma / Testicular Embryonal Carcinoma and Yolk Sac Tumor / Testicular Embryonal Carcinoma and Yolk Sac Tumor With Seminoma / Testicular Teratoma / Testicular Yolk Sac Tumor / Testicular Yolk Sac Tumor and Teratoma / Testicular Yolk Sac Tumor and Teratoma With Seminoma||1|
|1||Completed||Treatment||Lymphoma NOS / Neuroblastomas / Sarcomas / Wilms' tumor||1|
|1||Completed||Treatment||Transitional Cell Carcinoma||1|
|1||Not Yet Recruiting||Treatment||Advanced Cancers / Melanoma||1|
|1||Not Yet Recruiting||Treatment||Melanoma||1|
|1||Not Yet Recruiting||Treatment||Melanoma / Sarcomas||1|
|1||Not Yet Recruiting||Treatment||Non Small Cell Lung Cancer (NSCLC)||1|
|1||Recruiting||Basic Science||Advanced Melanoma / Metastatic Melanoma||1|
|1||Recruiting||Treatment||Adverse Effect of Radiation Therapy / Effects of Immunotherapy / Melanoma||1|
|1||Recruiting||Treatment||Melanoma / Skin Cancers||1|
|1||Recruiting||Treatment||Non-Small-Cell Lung Carcinoma (NSCLC)||1|
|1, 2||Active Not Recruiting||Treatment||Melanoma||1|
|1, 2||Active Not Recruiting||Treatment||Metastatic Melanoma||2|
|1, 2||Active Not Recruiting||Treatment||Prostate Cancers||1|
|1, 2||Completed||Treatment||Metastatic Melanoma||1|
|1, 2||Completed||Treatment||Neoplasms Metastasis / Prostate Cancers||1|
|1, 2||Completed||Treatment||Unresectable Stage III or IV Malignant Melanoma||1|
|1, 2||Not Yet Recruiting||Treatment||Immunotherapy / Neoplasms, Head and Neck||1|
|1, 2||Not Yet Recruiting||Treatment||Lymphoma NOS / Multiple Myeloma (MM)||1|
|1, 2||Not Yet Recruiting||Treatment||Metastatic Brain Cancer||1|
|1, 2||Not Yet Recruiting||Treatment||Prostate Cancers||1|
|1, 2||Recruiting||Treatment||Cancer, Advanced||1|
|1, 2||Recruiting||Treatment||Hepatocellular Carcinomas||1|
|1, 2||Recruiting||Treatment||Liver Cancer / Lung Cancers||1|
|1, 2||Recruiting||Treatment||Lymphoma NOS / Tumors, Solid||1|
|1, 2||Recruiting||Treatment||MSI Negative Colorectal Cancer / MSI Positive Colorectal Cancer||1|
|1, 2||Recruiting||Treatment||Malignant Melanoma||1|
|1, 2||Recruiting||Treatment||Melanoma / Metastatic (Stage IV) Melanoma / Unresectable (Stage III) Melanoma||1|
|1, 2||Recruiting||Treatment||Metastatic Melanoma||2|
|1, 2||Recruiting||Treatment||Metastatic Melanoma / Stage III Melanoma / Stage IV Melanoma||1|
|1, 2||Recruiting||Treatment||Stage III or IV Melanoma||1|
|1, 2||Recruiting||Treatment||Unresectable Stage III or Stage IV Melanoma||1|
|1, 2||Recruiting||Treatment||Various Advanced Cancer||1|
|1, 2||Withdrawn||Treatment||Metastatic Melanoma||1|
|2||Active Not Recruiting||Treatment||Carcinoma, Urothelial||1|
|2||Active Not Recruiting||Treatment||Metastatic Melanoma||2|
|2||Active Not Recruiting||Treatment||Metastatic Melanoma / Unresectable Melanoma||1|
|2||Active Not Recruiting||Treatment||Non-Small-Cell Lung Carcinoma (NSCLC)||1|
|2||Active Not Recruiting||Treatment||Prostate Cancers||2|
|2||Completed||Treatment||Adenocarcinomas / Cancer, Breast||1|
|2||Completed||Treatment||Brain Metastasis / Melanoma||1|
|2||Completed||Treatment||Lung Cancers / Non-Small-Cell Lung Carcinoma (NSCLC) / Small Cell Lung Cancer (SCLC)||1|
|2||Completed||Treatment||Metastatic Malignant Melanoma||1|
|2||Not Yet Recruiting||Treatment||Acral lentiginous melanoma / Mucosal Melanoma||1|
|2||Not Yet Recruiting||Treatment||Melanoma||1|
|2||Not Yet Recruiting||Treatment||Mesothelioma||1|
|2||Not Yet Recruiting||Treatment||Metastatic Melanoma||1|
|2||Not Yet Recruiting||Treatment||Prostate Cancers||1|
|2||Not Yet Recruiting||Treatment||Prostatic Neoplasms||1|
|2||Not Yet Recruiting||Treatment||Uveal Melanoma||1|
|2||Recruiting||Treatment||In-transit Metastases Melanoma Stage IIIB and IIIC||1|
|2||Recruiting||Treatment||Leukemias / Myelodysplastic Syndrome||1|
|2||Recruiting||Treatment||Limited Stage Small Cell Lung Cancer / Small Cell Lung Cancer (SCLC)||1|
|2||Recruiting||Treatment||Malignant Melanoma Stage III||1|
|2||Recruiting||Treatment||Melanoma / Metastases, Brain||2|
|2||Recruiting||Treatment||Melanoma / Oligometastatic Melanoma||1|
|2||Recruiting||Treatment||Melanoma / Uveal Melanoma||1|
|2||Recruiting||Treatment||Metastases, Brain / Metastatic Melanoma||1|
|2||Recruiting||Treatment||Metastatic Castration Sensitive Prostate Cancer||1|
|2||Recruiting||Treatment||Metastatic Melanoma / Stage IV Melanoma||1|
|2||Recruiting||Treatment||Metastatic Pancreatic Adenocarcinoma||1|
|2||Recruiting||Treatment||Neuroendocrine Carcinoma of the Skin||1|
|2||Recruiting||Treatment||Non Small Cell Lung Cancer (NSCLC)||1|
|2||Withdrawn||Treatment||Neuroendocrine Carcinoma of the Skin||1|
|3||Active Not Recruiting||Treatment||High Risk Stage III Melanoma||1|
|3||Active Not Recruiting||Treatment||Lung Cancer - Non Small Cell||1|
|3||Active Not Recruiting||Treatment||Melanoma||1|
|3||Completed||Treatment||Melanoma / Metastases||1|
|3||Recruiting||Treatment||Gastric Cancers / Gastroesophageal Junction Cancer||1|
|3||Recruiting||Treatment||Non-Small-Cell Lung Carcinoma (NSCLC)||1|
|4||Active Not Recruiting||Treatment||Malignant Melanoma||1|
|4||Recruiting||Treatment||Renal Cell Carcinoma (RCC)||1|
|Not Available||Available||Not Available||Malignant Melanoma||1|
|Not Available||Completed||Not Available||Advanced Melanoma||1|
|Not Available||Completed||Not Available||Melanoma||1|
|Not Available||No Longer Available||Not Available||Melanoma||1|
|Not Available||Recruiting||Not Available||Melanoma||2|
|Not Available||Recruiting||Treatment||Blood And Marrow Transplantation / Leukemias / Lymphoma NOS||1|
|Not Available||Recruiting||Treatment||Kidney Cancer||1|
|Not Available||Recruiting||Treatment||Metastatic Melanoma||1|
|Pharmacodynamics||The pharmacodynamics of Ipilimumab are not completely understood. In melanoma patients receiving Ipilimumab, the mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. This increase occurred in a dose-dependent fashion in Phase 2 studies.
Ipilimumab given with or without gp100 at 3 mg/kg increased ALC throughout the induction dosing period, but no meaningful change in ALC occurred in the control group who received an investigational peptide vaccine alone.
Furthermore, ipilimumab binds to CTLA-4 with high affinity (Kd = 5.24 ± 3.62 nM). As a result, ligands CD80 and CD86 are blocked from binding to CTLA-4 with a minimum EC50 value of 0.2 μg/mL. |
|Mechanism of action||Ipilimumab is a fully human IgG1κ antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on T-cells that is indicated for unresectable or metastatic melanoma. The absence or presence of CTLA-4 can augment or suppress the immune system's T-cell response in fighting disease. Ipilimumab is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells. The proposed mechanism of action is indirect, and may be through T-cell - mediated anti-tumor immune responses. |
|Target||Kind||Pharmacological action||Actions||Organism||UniProt ID|
|Cytotoxic T-lymphocyte protein 4||Protein||yes||Not Available||Human||P16410 ||details|
|Absorption||In one pharmacokinetic study of patients with unresectable or metastatic melanoma peak concentrations, trough concentrations, and area under the curve (AUC) were found to be dose proportional in the dosage range examined (0.3, 3, or 10mg/kg every 3 weeks for four doses). |
|Volume of distribution|
Volume of distribution at steady state = 7.21 L
|Protein binding||Not Available|
The metabolism of ipilimumab does not involve the cytochrome P450 enzyme system. Because ipilimumab is a protein it is expected to be degraded into small peptides and amino acids by proteolytic enzymes.
|Route of elimination||Not Available|
|Half life||Terminal Elimination Half-life: 14.7 -15.4 days
Clearance was measured to be 15.3mL/hr-16.8 mL/hr.
In one pharmacokinetic study examining ipilimumab administered every 3 weeks, clearance was found to be time invariant. Minimal systemic accumulation was observed (accumulation index of 1.5 fold or less).
Steady state concentrations was reached by the third dose.
Clearance will increase with increasing body weight; however, no dose adjustment is needed if administration occurs on a mg/kg basis. The following had no clinically meaningful influence on clearance: Age (range 26-86 years), gender, creatinine clearance (if ≥29ml/min), baseline AST, total bilirubin, ALT levels, concomitant use of budesonide, performance status, HLA-A2*0201 status, positive anti-ipilimumab antibody status, prior use of systemic anticancer therapy, baseline lactate dehydrogenase levels.
|Toxicity||Therapy with Ipilimumab can result in severe and fatal immune reactions due to T-cell proliferation and activation. These reactions may occur in multiple organ systems, but common reactions include enterecolitis, dermatitis (including toxic necrolysis), neuropathy, and endocrinopathy.
Patients should be assessed for signs and symptoms of enterocolitis (diarrhea, abdominal pain, mucus/blood in stool), bowel perforation (petitoneal signs and ileus), hepatitis, dermatitis (rash and pruritus), motor or sensory neuropathy (unilateral/bilateral weakness, sensory alterations, or paresthesia) , hypophysitis/adrenal insufficiency including adrenal crisis/hyper- or hypothyroidism (fatigue, mental status change, abdominal pain, unusual bowel habits, hypotension) and should have liver function tests and thyroid function tests performed at baseline and prior to each dose.
Typically immune mediated adverse reactions manifest during therapy, however, a minority of reactions occurred after discontinuation of ipilimumab.
In one study of neuropathies, one case of fatal Guillain-Barré syndrome occurred, and once case of severe peripheral neuropathy (Grade 3) was reported. During clinical development of ipilimumab additional cases of Guillain-Barré and myasthenia gravis have been reported. In severe neuropathy, permanently discontinue ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent.
In one study, severe or potentially fatal dermatitis (eg, Steven-Johnsons syndrome (SJS) or toxic epidermal necrolysis (TEN)) occured in 2.5% (n=13). The median time of onset of moderate to potentially fatal dermatitis was 3.1 weeks (up to 17.3 weeks). Treatment of 54% of severe dermatitis cases (n=7) involved high dose topical corticosteriods. 6 patients had complete resolution in up to 15.6 weeks. Permanently discontinue ipilimumab in patients with SJS or TEN, and withhold the dose in patients with moderate to severe signs and symptoms. Mild- moderate dermatitis (localized rash and pruritus) may be treated symptomatically. If no improvement is seen in 1 week administer topical or systemic corticosteroids.
In one study of endocrinopathies, severe to life threatening endocrinopathies occurred in 1.8% (n=9) of patients, with all 9 patients having hyopituitarism and some having adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized. Moderate endocrinopathies occurred in 2.3% of patients (n=12) and required hormone replacement or medical intervention. The median time of onset was 11 weeks. In symptomatic patients, withhold ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent and appropriate hormone replacement therapy.
In one study of enterocolitis in 511 patients, diarrhea of ≥7 stools above baseline, fever, ileus and peritoneal signs (Grade 3-5, severe, potentially fatal enterocolitis) occured in 7% (n=34) of patients treated with ipilimumab. Diarrhea of up to 6 stools above baseline, abdominal pain, mucus or blood in stool (Grade 2, moderate enterocolitis) occurred in 5% of patients (n=28). Intestinal perforation occurred in 1% (n=5). Death as a result of complications occurred in 0.8% (n=4). Hospitalization for severe enterocolitis occurred in 5% (n=26).
Grade 3-5 enterocolitis had a median time of onset of 7.4 weeks (with a range of 1.6-13.4 weeks).
Grade 2 entercolitis had a median time of onset of 6.3 weeks (with a range of 0.3- 18.9 weeks).
Treatment of 85% (n=29) of patients with Grade 3-5 enterocolitis (n=34) included high dose corticosteroids (≥40mg/day prednisone equivalent). Median dose used was 80mg/day of prednisone/equivalent for a median duration of 2.3 weeks (up to 13.9 weeks). Of the 34 patients, 74% experienced complete resolution, 3% progressed to Grade 2 severity, and 24% exhibited no improvement.
In treatment of 28 patients with a Grade 2 enterocolitis: 25% received high dose corticosteroids for a median of 10 days; 29% of patients received a non-high dose of corticosteroids (<40mg/day of prednisone/equivalent) for a median duration of 5.1 weeks; 46% did not receive systemic corticosteroids. Of the 28 patients, 79% of patients experienced complete resolution, 11% improved in severity, 11% exhibited no improvement.
In patients with severe enterocolitis, permanently discontinue ipilimumab, and initiate 1-2 mg/kd/day of prednisone or an equivalent. Once patient improvement to Grade 1 or less is seen, taper the corticosteroid over at least one month.
In patients with moderate enterocolitis, hold dose of ipilimumab, and initiate 0.5 mg/kd/day of prednisone or an equivalent.
In another study examining immune mediated hepatitis, AST or ALT elevation of ≥3 times the upper limit of normal (ULN) (severe and potentially fatal hepatotoxicity) was seen in 2% (n=8) of patients on ipilimumab. Fatal hepatic failure occurred in 0.2%. Hospitalization occurred in 0.4%. Additionally, moderate hepatotoxicity (2.5xULN >ALT or AST> 5xULN, or 1.5xULN>bilirubin>3xULN ) occurred in 2.5% (n=13).
In Grade 3-5 hepatotoxicity, permanently discontinue ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent. Once LFT show sustained improvement taper corticosteroid over 1 month. In Grade 2 hepatotoxicity, withhold ipilimumab.
In pregnancy, use only if potential benefit justifies potential risk to fetus (Category C). In studies done in monkeys, severe toxicities were observed including abortion, stillbirth, low birth weight and infant mortality. Additionally, ipilimumab has the potential to cross the placental barrier, and it is unknown if secretion into breast milk occurs.
No studies have been performed to study carcinogenesis, mutagenesis, and impairment of fertility. |
|SNP Mediated Effects||Not Available|
|SNP Mediated Adverse Drug Reactions||Not Available|
|Acetyldigitoxin||Acetyldigitoxin may decrease the cardiotoxic activities of Ipilimumab.||Approved|
|ALT-110||The therapeutic efficacy of ALT-110 can be decreased when used in combination with Ipilimumab.||Investigational|
|Anvirzel||Anvirzel may decrease the cardiotoxic activities of Ipilimumab.||Investigational|
|Belimumab||The risk or severity of adverse effects can be increased when Ipilimumab is combined with Belimumab.||Approved|
|Bevacizumab||Bevacizumab may increase the cardiotoxic activities of Ipilimumab.||Approved, Investigational|
|Cabazitaxel||The risk or severity of adverse effects can be increased when Cabazitaxel is combined with Ipilimumab.||Approved|
|CDX-110||The therapeutic efficacy of CDX-110 can be decreased when used in combination with Ipilimumab.||Investigational|
|Cyclophosphamide||Cyclophosphamide may increase the cardiotoxic activities of Ipilimumab.||Approved, Investigational|
|Deslanoside||Deslanoside may decrease the cardiotoxic activities of Ipilimumab.||Approved|
|Digitoxin||Digitoxin may decrease the cardiotoxic activities of Ipilimumab.||Approved|
|Digoxin||Digoxin may decrease the cardiotoxic activities of Ipilimumab.||Approved|
|Docetaxel||The risk or severity of adverse effects can be increased when Docetaxel is combined with Ipilimumab.||Approved, Investigational|
|G17DT||The therapeutic efficacy of G17DT can be decreased when used in combination with Ipilimumab.||Investigational|
|GI-5005||The therapeutic efficacy of GI-5005 can be decreased when used in combination with Ipilimumab.||Investigational|
|INGN 201||The therapeutic efficacy of INGN 201 can be decreased when used in combination with Ipilimumab.||Investigational|
|INGN 225||The therapeutic efficacy of INGN 225 can be decreased when used in combination with Ipilimumab.||Investigational|
|Ouabain||Ouabain may decrease the cardiotoxic activities of Ipilimumab.||Approved|
|Paclitaxel||The risk or severity of adverse effects can be increased when Paclitaxel is combined with Ipilimumab.||Approved, Vet Approved|
|Rabies vaccine||The therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Ipilimumab.||Approved|
|SRP 299||The therapeutic efficacy of SRP 299 can be decreased when used in combination with Ipilimumab.||Investigational|
|TG4010||The therapeutic efficacy of TG4010 can be decreased when used in combination with Ipilimumab.||Investigational|
|Trastuzumab||Trastuzumab may increase the cardiotoxic activities of Ipilimumab.||Approved, Investigational|
|Vemurafenib||Ipilimumab may increase the hepatotoxic activities of Vemurafenib.||Approved|
|Food Interactions||Not Available|
|Synthesis Reference||Not Available|
- Ribas A: Tumor immunotherapy directed at PD-1. N Engl J Med. 2012 Jun 28;366(26):2517-9. doi: 10.1056/NEJMe1205943. Epub 2012 Jun 2. [PubMed:22658126 ]
|PDB Entries||Not Available|
|FDA label||Download (374 KB) |
|MSDS||Download (479 KB) |
|Patent Number||Pediatric Extension||Approved||Expires (estimated)|
|Experimental Properties||Not Available|
|Super Class||Organic Acids|
|Class||Carboxylic Acids and Derivatives|
|Sub Class||Amino Acids, Peptides, and Analogues|
|Alternative Parents||Not Available|
|Molecular Framework||Not Available|
|External Descriptors||Not Available|