Siltuximab, a recombinant chimeric (human-murine) monoclonal antibody and interleukin-6 (IL-6) antagonist, is an antineoplastic agent.1, 2, 4, 5, 13, 19, 20, 23
Multicentric Castleman's Disease
Siltuximab is used for the treatment of multicentric Castleman's disease (MCD) in patients who are human immunodeficiency virus (HIV)-negative and human herpes virus type 8 (HHV-8)-negative;1, 2 siltuximab is designated an orphan drug by the FDA for the treatment of this disease.3
MCD is a rare lymphoproliferative disorder that is associated with excessive release of interleukin-6 (IL-6) and other proinflammatory cytokines.5, 17, 18, 20, 23 The disease usually affects adults.17, 18 Although the pathogenesis of MCD is not fully understood, excessive production and dysregulation of IL-6 appear to play a prominent role in the multicentric form of the disease, and lead to stimulation of the production of acute phase reactants in the liver.5, 17, 20 As a result, patients with MCD often experience systemic manifestations such as fever, night sweats, anorexia, weight loss, weakness and fatigue, edema, effusions, pruritus, pain, and/or dyspnea.5, 17, 18, 20 Laboratory abnormalities, such as anemia, elevated concentrations of inflammatory markers (e.g., C-reactive protein), hypergammaglobulinemia, and hypoalbuminemia, also may be present.5, 17, 20 (See Description.)
The current indication for siltuximab is based principally on the results of a randomized, double-blind, placebo-controlled, multinational phase 2 study in adults with MCD who were HIV-negative and HHV-8-negative.1, 2 A total of 79 patients with symptomatic MCD were randomized (2:1) to receive siltuximab plus best supportive care or to placebo plus best supportive care in this study.1, 2 Best supportive care included management of effusions; use of antipyretic, antipruritic, antihistamine, and analgesic medications; management of infections; transfusions; and standard treatment of infusion-related reactions.2 Siltuximab was given in a dosage of 11 mg/kg by IV infusion every 3 weeks until treatment failure (defined as disease progression based on increased symptoms, radiologic progression, or deterioration in performance status) or unacceptable toxicity.1, 2 The primary measure of efficacy was durable tumor and symptomatic response, which was defined as tumor response assessed by independent review and complete resolution or stabilization of disease-related symptoms for at least 18 weeks without treatment failure.1, 2 Upon treatment failure, patients previously randomized to receive placebo were permitted to cross over to open-label siltuximab treatment.2 The median patient age in the study was 48 years (range: 20-78 years); the histologic subtype of MCD was similar in both treatment arms, with 33% hyaline vascular subtype, 23% plasmacytic subtype, and 44% mixed subtype.1, 2 At baseline, 55 and 65% of the patients in the siltuximab and placebo arms, respectively, had received prior systemic therapies for their disease and 25 and 35% of the patients in the siltuximab and placebo arms, respectively, were concurrently receiving corticosteroid therapy.2 Durable tumor and symptomatic response was observed in 34% of patients receiving siltuximab compared with none of those receiving placebo.1, 2 Tumor response rates also were substantially higher in patients receiving siltuximab compared with those receiving placebo (38 versus 4%).1, 2 At the time of analysis, median time to treatment failure had not been reached in patients receiving siltuximab; however, the median time to treatment failure was 134 days in patients receiving placebo.1 In addition, in patients who were anemic when entering the study, hemoglobin concentrations increased by at least 1.5 g/dL following 13 weeks of therapy in 61% of siltuximab-treated patients compared with none of those receiving placebo.1, 2
In a separate analysis of patient-reported outcomes (e.g., patient perception of symptoms, functional status, and well being) from this study, the siltuximab-treated patients reported substantial and durable improvements in fatigue compared with those receiving placebo.15 Fatigue was improved at the end of the first cycle of therapy and continued to improve throughout the study.15 In addition, patients receiving siltuximab experienced significant improvement from baseline in most of the domains assessed by the Short Form-36 (SF-36) Health Survey (physical, role emotional, vitality, bodily pain, and mental health domains).15
In an interim analysis of a long-term extension study of siltuximab therapy in 19 patients with MCD, patients who had received in total a median of 81 doses of the drug over a median follow-up period of 5.1 years were all alive and control of their disease was maintained.24 Chronic siltuximab therapy was well tolerated, and there was no evidence of new or cumulative toxicity.24
The manufacturer states that siltuximab was not studied in HIV- and HHV-8-positive patients with MCD† because the drug did not bind to virally produced IL-6 in a nonclinical study.1 (See Description.) However, it has been suggested by some clinicians that anti-IL6 therapy may still help to decrease the activity of human IL-6, which is elevated in most patients with HIV-associated MCD, and thereby help to control the disease.17, 20, 21, 22 There currently is very little experience treating HIV- and HHV-8-associated MCD with anti-IL-6 therapy.17, 20, 21, 22 Clinical trials are needed to determine whether siltuximab is effective in this population.17, 20
Because of the risk of infusion-related reactions and hypersensitivity, siltuximab should be administered in a setting in which resuscitation equipment, medications, and personnel trained to provide resuscitation are available.1 (See Infusion-related Reactions and Hypersensitivity under Cautions: Warnings/Precautions.)
Complete blood cell (CBC) counts should be obtained prior to each dose of siltuximab for the first 12 months of therapy and then every 3 cycles thereafter.1 Clinicians should be aware that siltuximab therapy may increase hemoglobin concentrations in patients with multicentric Castleman's disease (MCD).1 (See Hematologic Toxicity under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.)
Siltuximab should not be administered to patients with severe infections until the infection resolves.1 (See Concurrent Active Severe Infections under Cautions: Warnings/Precautions.)
Siltuximab is administered by IV infusion over 60 minutes.1
Unopened vials of siltuximab lyophilized powder for injection should be protected from light and stored at 2-8°C.1
Prior to administration, commercially available siltuximab lyophilized powder for injection must be reconstituted and diluted using proper aseptic technique.1 Based on the indicated dosage of siltuximab, the appropriate number of vials of the drug should be reconstituted.1 The vials containing siltuximab lyophilized powder should be removed from the refrigerator and allowed to come to room temperature (15-25°C) over approximately 30 minutes prior to reconstitution; the drug should remain at room temperature for the duration of the preparation.1 A 21-gauge, 1.5-inch needle is recommended by the manufacturer for preparation.1 The lyophilized powder is reconstituted by adding 5.2 mL of sterile water for injection to a vial labeled as containing 100 mg of siltuximab or by adding 20 mL of sterile water for injection to a vial labeled as containing 400 mg of siltuximab to provide a solution containing 20 mg/mL.1 The vials should then be gently swirled to facilitate dissolution of the lyophilized powder, which should dissolve in less than 1 hour.1 The vials should not be shaken or swirled vigorously.1 The contents of the reconstituted vials should not be removed until all of the solids have completely dissolved.1 The reconstituted solution should be inspected visually for particulate matter and discoloration prior to dilution and should not be used if particles are present or if the solution appears discolored or visibly opaque.1 The reconstituted siltuximab solution should be kept at room temperature for no more than 2 hours prior to addition into the infusion bag.1
Reconstituted siltuximab solution should then be diluted in 5% dextrose injection to provide a total volume of 250 mL (i.e., if a 250-mL bag of 5% dextrose injection is used, a volume of the diluent equal to the total required volume of reconstituted siltuximab solution should be removed from the bag prior to addition of the reconstituted siltuximab solution).1 The total required volume of reconstituted siltuximab solution should then be added slowly to the diluent in a diethylhexyl phthalate (DEHP)-plasticized polyvinylchloride (PVC) or non-PVC (polyolefin) infusion bag.1 The diluted solution should then be mixed by gentle inversion.1 Diluted infusion solutions of the drug are stable for up to 4 hours after dilution of the reconstituted solution (including infusion time) when stored at room temperature.1 Siltuximab infusion solution should be administered by IV infusion through a 0.2-µm inline polyethersulfone filter.1 The diluted infusion solution should be administered through PVC- or polyurethane-lined administration sets.1
Siltuximab should not be administered simultaneously through the same IV line with any other drug.1 Commercially available vials of siltuximab for injection contain no preservatives and are intended for single use only; any unused portions of the reconstituted or diluted solutions should be discarded.1 Procedures for proper disposal should be followed.1
Multicentric Castleman's Disease
For the treatment of MCD in adults who are human immunodeficiency virus (HIV)-negative and human herpes virus type 8 (HHV-8)-negative, the recommended dosage of siltuximab is 11 mg/kg administered as a 60-minute infusion every 3 weeks.1 Therapy should be continued until treatment failure (i.e., disease progression based on increased symptoms, radiologic progression, or deterioration in performance status) occurs.1
Therapy Interruption for Toxicity
A delay in administration of the first dose of siltuximab should be considered in patients with an absolute neutrophil count (ANC) of less than 1000/mm3, platelet count of less than 75,000/mm3, and/or hemoglobin concentration of 17 g/dL or more.1 The dosage of siltuximab should not be reduced in such cases.1
For subsequent doses, the manufacturer recommends that a delay in therapy be considered if the ANC is less than 1000/mm3, the platelet count is less than 50,000/mm3, and/or the hemoglobin concentration is 17 g/dL or more.1 The dosage of siltuximab should not be reduced in such cases.1
Infusion-related Reactions and Hypersensitivity
If mild to moderate infusion-related reactions occur, the siltuximab infusion should be temporarily interrupted.1 If the reaction resolves, the infusion may be resumed at a slower infusion rate.1 Treatment with antihistamines, acetaminophen, and/or corticosteroids should be considered in such cases.1 Siltuximab should be discontinued if the patient is unable to tolerate the infusion following these interventions.1
If severe infusion-related reactions or cytokine release syndromes occur, therapy with the drug should be permanently discontinued.1
Siltuximab should be immediately and permanently discontinued in patients who experience anaphylaxis.1 (See Cautions: Contraindications and also see Infusion-related Reactions and Hypersensitivity under Cautions: Warnings/Precautions.)
No initial dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 The manufacturer currently does not provide dosage recommendations for patients with severe hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
In patients with renal impairment, no initial dosage adjustment is necessary in patients with a creatinine clearance of 15 mL/minute or greater.1 The manufacturer currently does not provide dosage recommendations for patients with a creatinine clearance of less than 15 mL/minute and for patients with end-stage renal disease.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Severe hypersensitivity reaction to siltuximab or any ingredient in the formulation.1 (See Infusion-related Reactions and Hypersensitivity under Cautions: Warnings/Precautions.)
Concurrent Active Severe Infections
Siltuximab may mask signs and symptoms of acute inflammation (i.e., suppression of fever and acute phase reactants such as C-reactive protein [CRP]).1
Siltuximab should not be used in patients with severe infections until the infection has resolved.1
Patients receiving siltuximab should be closely monitored for possible infections.1 If an infection develops, anti-infective therapy should be initiated promptly and siltuximab therapy should be withheld until the infection resolves.1
Because inhibition of interleukin-6 (IL-6) may interfere with the normal immune response to new antigens, live vaccines should not be administered to patients receiving siltuximab.1 (See Advice to Patients.)
Infusion-related Reactions and Hypersensitivity
Anaphylactic reaction occurred in 1 of 750 siltuximab-treated patients.1 If signs of anaphylaxis or other severe allergic reactions occur, the infusion of siltuximab should be discontinued and no further therapy with the drug should be given.1 (See Contraindications under Cautions.)
Infusion-related reactions were reported in 4.8% of patients receiving siltuximab monotherapy.1 Manifestations include back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations.1
In patients experiencing mild or moderate infusion-related reactions, temporary interruption of the siltuximab infusion is recommended.1 If the reaction resolves, the infusion may be resumed at a slower infusion rate.1 Treatment with antihistamines, acetaminophen, and corticosteroids should be considered in such cases.1 Siltuximab should be discontinued if the patient is unable to tolerate the infusion following these interventions.1
If severe infusion-related reactions or cytokine release syndromes occur, siltuximab therapy should be permanently discontinued.1
GI perforation has occurred in patients receiving siltuximab in clinical trials; however, no cases were reported in multicentric Castleman's disease (MCD) trials of the drug.1
Siltuximab should be used with caution in patients who may be at increased risk for GI perforation (e.g., those with diverticulitis or ulcers).1 Patients should be evaluated promptly if symptoms associated with or suggestive of GI perforation occur (e.g., stomach pain, nausea, change in bowel habits, fever).1, 19
There is a potential for immunogenicity with siltuximab therapy.1 Anti-siltuximab antibodies were detected by enzyme immunoassay (EIA) and electrochemiluminescence-based immunoassay (ECLIA) methods in 1 of 411 patients (0.2%) treated with siltuximab in clinical studies.1 Further analyses of the single positive sample indicated a low titer of anti-siltuximab antibodies with non-neutralizing capabilities.1 No evidence of altered toxicity of the drug was observed in the patient who developed the antibodies.1
There are no adequate and well-controlled studies in pregnant women.1 Maternal and fetal toxicity was not observed when siltuximab was administered to pregnant animals; however, siltuximab crossed the placenta and fetal serum concentrations were similar to maternal concentrations.1 Administration of a human antibody to IL-6 to pregnant animals caused decreased globulin concentrations in pregnant animals and offspring.1
Infants born to pregnant women treated with siltuximab may be at an increased risk of infection; therefore, caution is advised in the administration of live vaccines in these infants.1 Pregnancy should be avoided during siltuximab therapy.1 The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1 Women of childbearing potential should use contraception during siltuximab treatment and for 3 months following discontinuance of the drug.1
It is not known whether siltuximab is distributed into human milk or absorbed systemically after ingestion.1 Because many drugs and immunoglobulins are distributed into human milk and because of the potential for adverse reactions to siltuximab in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
MCD usually affects adults.17, 18 Safety and efficacy of siltuximab have not been established in pediatric patients younger than 18 years of age.1, 2
In clinical trials evaluating siltuximab as single-agent therapy, 35% of patients were 65 years of age or older.1 Although no overall differences in safety were observed between geriatric patients and younger adults in these clinical trials and in other clinical experience, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.1 Clinical studies evaluating siltuximab for the treatment of MCD did not include sufficient numbers of patients 65 years of age and older to determine the effect of age on the drug's efficacy for this condition.1
In a population pharmacokinetic analysis, age (range: 18-85 years) did not affect exposure of siltuximab.1
A population pharmacokinetic analysis of data from 377 patients enrolled in siltuximab clinical trials indicates that clearance of the drug is similar in patients with preexisting mild or moderate hepatic impairment (Child-Pugh class A or B) and those with normal hepatic function.1 Patients with severe hepatic impairment (Child-Pugh class C) were excluded from clinical studies of the drug.1
Analysis of population pharmacokinetic data from 377 patients enrolled in siltuximab clinical trials indicates that clearance of the drug is similar in patients with preexisting mild, moderate, or severe renal impairment (creatinine clearance 15-89 mL/minute) and those with normal renal function.1 The potential effect of end-stage renal disease on siltuximab pharmacokinetics is not known since clinical and pharmacokinetic data are very limited.1 (See Dosage and Administration: Special Populations.)
Adverse effects reported in more than 10% of patients receiving siltuximab for the treatment of MCD and at an incidence that is at least 10% higher than that reported with placebo include rash (e.g., maculopapular, papular, generalized, pruritic),1, 2 pruritus,1, 2 upper respiratory tract infection,1, 2 weight gain,1, 2 localized edema,2 abdominal pain,2 thrombocytopenia,2 nasopharyngitis,2 and hyperuricemia.1, 2
Formal drug interaction studies have not been conducted to date with siltuximab.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Possible increased metabolism of drugs that are metabolized by cytochrome P-450 (CYP) isoenzymes.1 Because cytokines such as interleukin-6 (IL-6) may downregulate CYP enzymes, inhibition of IL-6 by siltuximab may restore CYP enzyme activity to higher levels.1 Effects of siltuximab on CYP enzyme activity may persist for several weeks after the drug is discontinued.1
Following initiation or discontinuance of siltuximab therapy, patients receiving certain drugs metabolized by CYP isoenzymes (i.e., those with a low therapeutic index that require individualized dosing [e.g., cyclosporine, theophylline, warfarin]) should be monitored for therapeutic effect and/or changes in serum concentrations, and dosages of these drugs should be adjusted as needed.1 Caution also is advised when siltuximab is used concomitantly with CYP3A4 substrates (e.g., oral contraceptives, atorvastatin, lovastatin) for which a reduction in efficacy would be undesirable.1
Live vaccines should not be administered to patients receiving siltuximab.1 (See Immunization under Cautions: Warnings/Precautions.)
Siltuximab is a recombinant chimeric (human-murine) monoclonal antibody specific for human interleukin-6 (IL-6) that is produced in Chinese hamster ovary cells.1, 2, 4, 5, 13, 19, 20, 23 The drug is an IgG1 kappa immunoglobulin that binds human IL-6 and thereby prevents its binding to both soluble and membrane-bound IL-6 receptors.1, 2, 4, 5, 13, 14, 19 IL-6 is known to be involved in a variety of normal physiologic processes including induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and cell proliferation and differentiation.1, 2, 4, 5, 13, 14, 19
Overproduction of IL-6 appears to play a critical role in the disease process of multicentric Castleman's disease (MCD),1, 4, 13, 19 resulting in plasma cell proliferation and a variety of systemic manifestations (e.g., lymphadenopathy, hepatosplenomegaly, ascites, pleural effusion, edema, fever, fatigue, night sweats, anorexia, cachexia, anemia, pain, pruritus, sensory neuropathy).1, 4, 14, 15, 19 Although the cause of MCD in patients who are not infected with human immunodeficiency virus (HIV) and human herpes virus type 8 (HHV-8) has not been fully elucidated, HHV-8 is a well established cause of hypercytokinemia in HIV-infected and in some HIV-negative patients with MCD.15, 16 Siltuximab did not bind to virally produced IL-6 in a nonclinical study.1 (See Uses: Multicentric Castleman's Disease.)
Pharmacokinetics of siltuximab are approximately proportional to dose over the dosage range of 2.8-11 mg/kg given by IV infusion every 3 weeks.1 When given as an IV infusion once every 3 weeks, steady-state concentrations of siltuximab are achieved by the sixth infusion (within 18 weeks); systemic accumulation of the drug is approximately 1.7-fold higher at steady state when compared with single-dose administration.1 The dosage of siltuximab is based on body weight because body weight was the only significant covariate for clearance of the drug in a population pharmacokinetic analysis.1 The mean terminal half-life of siltuximab following the first IV infusion is 20.6 days.1
Importance of advising patients about potential benefits and risks of siltuximab.1 Importance of patients reading the manufacturer's patient information prior to initiation of therapy and each time they receive an infusion of the drug.1
Risk of increased susceptibility to infection.1 Importance of instructing patients to immediately contact their clinician if they develop symptoms suggesting an infection in order to ensure rapid evaluation and appropriate treatment.1
Importance of advising patients that they should not receive live vaccines during siltuximab therapy.1 Importance of informing clinician of recent or scheduled vaccinations and of discussing recommended vaccinations with their clinician prior to beginning siltuximab therapy.1
Risk of infusion-related and allergic reactions.1 Importance of immediately reporting signs and symptoms of such reactions, including dizziness, lightheadedness, wheezing, swelling of the lips, rash, breathing difficulty, or chest pain or tightness.1
Importance of advising patients to report any new or worsening medical conditions to their clinician.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of advising women not to breast-feed during therapy.1 Necessity of advising women of childbearing potential to use effective contraception while receiving siltuximab and for 3 months after the drug is discontinued.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., infections, GI disease).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 100 mg | ||
400 mg | Sylvant® | Janssen Biotech |
1. Janssen Biotech, Inc. Sylvant® (siltuximab) for injection prescribing information. Horsham, PA; 2014 Jun.
2. van Rhee F, Wong RS, Munshi N et al. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol . 2014; 15:966-74. [PubMed 25042199]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2015 Apr 27. [Web]
4. Barquero N. Siltuximab: a new option for the management of Castleman's disease. Drugs Today (Barc) . 2015; 51:21-8. [PubMed 25685858]
5. Deisseroth A, Ko CW, Nie L et al. FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease. Clin Cancer Res . 2015; 21:950-4. [PubMed 25601959]
13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125496Orig1s000: Pharmacology review(s). From FDA website. [Web]
14. van Rhee F, Fayad L, Voorhees P et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. J Clin Oncol . 2010; 28:3701-8. [PubMed 20625121]
15. van Rhee F, Rothman M, Ho KF et al. Patient-reported outcomes for multicentric Castleman's disease in a randomized, placebo-controlled study of siltuximab. Patient . 2015; 8:207-16. [PubMedCentral][PubMed 25736164]
16. Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood . 2014; 123:2924-33. [PubMed 24622327]
17. Soumerai JD, Sohani AR, Abramson JS. Diagnosis and management of Castleman disease. Cancer Control . 2014; 21:. [PubMed 25310208]
18. US Food and Drug Administration. FDA news release: FDA approves Sylvant for rare Castleman's disease. From FDA website. 2014 Apr 23. [Web]
19. Janssen-Cilag Ltd. Sylvant® (siltuximab) 400 mg powder for concentrate for solution for infusion summary of product characteristics. 2015 Jan 28. [Web]
20. Liu Y-C, Stone K, van Rhee F. Siltuximab for multicentric Castleman disease. Expert Rev Hematol . 2014; 7:545-57. [PubMed 25110138]
21. Nagao A, Nakazawa S, Hanabusa H. Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases. J Hematol Oncology . 2014; 7:10.
22. Muzes G, Sipos F, Csomor J et al. Successful tocilizumab treatment in a patient with human herpesvirus 8-positive and human immunodeficiency virus-negative multicentric Castleman's disease of plasma cell type nonresponsive to rituximab-CVP therapy. APMIS . 2013; 121:668-74. [PubMed 23163599]
23. Anon. Siltuximab (Sylvant) for treatment of multicentric Castleman's disease. Med Lett Drugs Ther . 2015; 57:e8.
24. van Rhee F, Casper C, Voorhees PM et al. An open-label, phase 2, multicenter study of the safely of long-term treatment with siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman's disease. Blood . 2013; 122:1806.