Molgramostim

(BAN, USAN, rINN)
Synonyms: Molgramostiimi; Molgramostimum; Sch-39300. A recombinant human granulocyte-macrophage colony-stimulating factor; Colony-stimulating factor 2 (human clone pHG 25 protein moiety reduced).
Cyrillic synonym: Молграмостим.

💊 Chemical information

CAS — 99283-10-0.
ATC — L03AA03.
ATC Vet — QL03AA03.

Pharmacopoeias.

Eur. includes a concentrated solution.

Ph. Eur. 6.2

(Molgramostim Concentrated Solution; Molgramostimi Solutio Concentrata). A solution of a protein having the structure of the granulocyte-macrophage colony-stimulating factor which is produced and secreted by various human blood cell types. It contains not less than 2.0 mg of protein per mL. A clear, colourless liquid. Store in airtight containers at a temperature below −65°. Protect from light.

Stability.

Solutions of molgramostim may be adsorbed onto glass and plastic materials and therefore should not be diluted below the recommended minimum concentration of 7 micrograms/mL.

💊 Adverse Effects

Granulocyte-macrophage colony-stimulating factors such as molgramostim may cause transient hypotension and flushing, bone pain and musculoskeletal pain, fever and chills, dyspnoea, rash, fatigue, and gastrointestinal effects. Antibodies have been detected. Anaphylactic reactions, pleural and pericardial effusion, and cardiac arrhythmias have been reported rarely. Colony-stimulating factors are fetotoxic in animal studies.
1. Vial T, Descotes J. Clinical toxicity of cytokines used as haemopoietic growth factors. Drug Safety 1995; 13: 371–406
2. Moleski RJ. Comparison of G-CSF and GM-CSF adverse event profiles in office-based practices: preliminary study results. Pharmacotherapy 2000; 20 (suppl): 112S–117S
3. Milkovich G, et al. Comparative safety of filgrastim versus sargramostim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy 2000; 20: 1432–40.

Antibodies.

Antibodies can develop in patients given recombinant granulocyte-macrophage colony-stimulating factors. The antibodies have been reported to occur more commonly, and in higher titres, in patients who are not immunocompromised compared with those who are.1,2 Although some binding antibodies are non-neutralising and have no apparent clinical effect,3 neutralising antibodies can reduce the efficacy of the colony-stimulating factor in repeated treatment cycles.1,2 However, antibodies have been reported to become undetectable after a number of weeks2 and do not appear to have long-term effects.1 Cross-reactivity between different granulocyte-macrophage colony-stimulating factors has been reported,1-3 and antibody formation may also be product dependent.2
1. Ragnhammar P, et al. Induction of anti-recombinant human granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients. Blood 1994; 84: 4078–87
2. Wadhwa M, et al. Immunogenicity of granulocyte-macrophage colony-stimulating factor (GM-CSF) products in patients undergoing combination therapy with GM-CSF. Clin Cancer Res 1999; 5: 1353–61
3. Ullenhag G, et al. Incidence of GM-CSF antibodies in cancer patients receiving GM-CSF for immunostimulation. Clin Immunol 2001; 99: 65–74.

Effects on the skin.

See under Filgrastim.

Effects on the thyroid.

See under Filgrastim.

💊 Precautions

Since granulocyte-macrophage colony-stimulating factors such as molgramostim can promote growth of myeloid cells in vitro their use in myeloid malignancies has been contra-indicated, although recently colony-stimulating factors have been used in some patients with myeloid diseases without stimulation of malignant cells. However, caution is required when they are used in patients with any pre-malignant or malignant myeloid condition. They should not be used from 24 hours before until 24 hours after cytotoxic chemotherapy or radiotherapy because of the sensitivity of rapidly dividing myeloid cells. Granulocyte-macrophage colony-stimulating factors should be used with caution in patients with pulmonary disease as they may be predisposed to dyspnoea. Treatment should be withdrawn in patients who develop signs of pulmonary infiltrates. Caution is also necessary in patients with fluid retention or heart failure as fluid retention may be aggravated. The complete blood count should be monitored regularly during therapy.

💊 Uses and Administration

Molgramostim is a granulocyte-macrophage colony-stimulating factor (GM-CSF), a haematopoietic growth factor that stimulates the development of white blood cells, particularly granulocytes, macrophages, and monocytes. It is used to treat or prevent neutropenia in patients receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia in patients undergoing bone marrow transplantation. It has also been used to reduce ganciclovir-induced neutropenia. As an adjunct to antineoplastic therapy, molgramostim is given by subcutaneous injection, starting 24 hours after the last dose of antineoplastic, in a dose of 5 to 10 micrograms/kg (60 000 to 110 000 international units/kg) daily. Treatment should be continued for 7 to 10 days. Following bone marrow transplantation, molgramostim may be given by intravenous infusion over 4 to 6 hours in a dose of 10 micrograms/kg (110 000 international units/kg) daily. Treatment should be begun the day after bone marrow transplantation and continued for up to 30 days depending on the neutrophil count. For the management of ganciclovir-induced neutropenia, molgramostim has been given by subcutaneous injection in a dose of 5 micrograms/kg (60 000 international units/kg) daily. After 5 doses have been given the dose of molgramostim should be adjusted according to the neutrophil count. The maximum dose for any indication should not exceed 10 micrograms/kg (110 000 international units/kg) daily. Granulocyte colony-stimulating factors such as filgrastim and macrophage colony-stimulating factors such as mirimostim are also used.
1. Armitage JO. Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1998; 92: 4491–4508
2. Mangi MH, Newland AC. Febrile neutropenia: prophylactic and therapeutic use of GM-CSF. Eur J Cancer 1999; 35 (suppl): S4–S7
3. Croockewit S. GM-CSF in haematopoietic stem cell transplantation. Eur J Cancer 1999; 35 (suppl): S11–S13
4. Sung L, et al. Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized controlled trials. J Clin Oncol 2004; 22: 3350–6
5. Smith TJ, et al. 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187–3205. Also available at: http://www.jco.org/cgi/reprint/24/19/3187 (accessed 20/09/06)

Infections.

See under Filgrastim, and under HIV Infection and AIDS in Sargramostim.

Ischaemia.

For mention of the use of molgramostim in patients with atherosclerotic coronary artery disease see under Filgrastim.

Respiratory disorders.

Pulmonary alveolar proteinosis is a rare diffuse lung disease that may result from impaired alveolar macrophage function caused by neutralising autoantibodies. It is characterised by excessive surfactant accumulation, and is usually managed with whole-lung lavage. Several months of therapy with subcutaneous granulocyte-macrophage colony-stimulating factor, typically in doses of 5 or 6 micrograms/kg daily, has been reported to induce remission in a number of these patients.1-6There has also been a case report7 of the effective use of inhaled granulocyte-macrophage colony-stimulating factor.
1. Barraclough RM, Gillies AJ. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax 2001; 56: 664–5
2. Seymour JF, et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med 2001; 163: 524–31
3. Schoch OD, et al. BAL findings in a patient with pulmonary alveolar proteinosis successfully treated with GM-CSF. Thorax 2002; 57: 277–80
4. Romero A, et al. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax 2002; 57: 837
5. Khanjari F, et al. GM-CSF and proteinosis. Thorax 2003; 58: 645
6. Abdul Rahman JA, et al. Pulmonary alveolar proteinosis associated with psoriasis and complicated by mycobacterial infection: successful treatment with granulocyte-macrophage colony stimulating factor after a partial response to whole lung lavage. Respirology 2004; 9: 419–22
7. Arai T, et al. Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF. Respir Med 2004; 98: 1227–30.

Wounds and ulcers.

Macrophages and granulocyte-macrophage colony-stimulating factors play important roles in several mechanisms essential to wound healing.1 Recombinant granulocyte-macrophage colony-stimulating factors are being tried in non-healing wounds and ulcers, particularly chronic venous leg ulcers. They have been given by perilesional subcutaneous injection and topical application in a few small studies and case reports with apparent promotion of wound healing.1 In a study2 of patients with pressure ulcers, healing was better during a 35-day period of treatment with granulocyte-macrophage colony-stimulating factor compared with placebo. However, a year after the treatment period there was no difference.3 In a group of 3 patients with inherited disorders of neutrophil function, topical sargramostim was reported to be of benefit in wound healing.4 In 1 case sargramostim was also given by continuous subcutaneous infusion for 72 hours into the surgical site of a gastrostomy closure. Topical molgramostim has also been used to promote healing of sickle-cell leg ulcers.5 Molgramostim has been used as a mouthwash to relieve severe recurrent aphthous mouth ulcers in a small number of patients with AIDS.6 There has also been some investigation of the use of granulocyte-macrophage colony-stimulating factor for oral mucositis in cancer patients, particularly those undergoing radiotherapy for head and neck cancers. Small studies of subcutaneous injection or topical application as a mouthwash have provided some optimistic results.7,8 Comparative studies, however, have found molgramostim to be no better than hydrocortisone mouthwash9 and perhaps only slightly better than sucralfate mouthwash.10
1. Groves RW, Schmidt-Lucke JA. Recombinant human GM-CSF in the treatment of poorly healing wounds. Adv Skin Wound Care 2000; 13: 107–12
2. Robson MC, et al. Sequential cytokine therapy for pressure ulcers: clinical and mechanistic response. Ann Surg 2000; 231: 600–611
3. Payne WG, et al. Long-term outcome study of growth factortreated pressure ulcers. Am J Surg 2001; 181: 81–6
4. De Ugarte DA, et al. Treatment of chronic wounds by local delivery of granulocyte-macrophage colony-stimulating factor in patients with neutrophil dysfunction. Pediatr Surg Int 2002; 18: 517–20
5. Méry L, et al. Topical effectiveness of molgramostim (GMCSF) in sickle cell leg ulcers. Dermatology 2004; 208: 135–7
6. Herranz P, et al. Successful treatment of aphthous ulcerations in AIDS patients using topical granulocyte-macrophage colonystimulating factor. Br J Dermatol 2000; 142: 171–6
7. Fung SM, Ferrill MJ. Granulocyte macrophage-colony stimulating factor and oral mucositis. Ann Pharmacother 2002; 36: 517–20
8. Mantovani G, et al. Phase II clinical trial of local use of GMCSF for prevention and treatment of chemotherapy- and concomitant chemoradiotherapy-induced severe oral mucositis in advanced head and neck cancer patients: an evaluation of effectiveness, safety and costs. Oncol Rep 2003; 10: 197–206
9. Sprinzl GM, et al. Local application of granulocyte-macrophage colony stimulating factor (GM-CSF) for the treatment of oral mucositis. Eur J Cancer 2001; 37: 2003–9
10. Saarilahti K, et al. Comparison of granulocyte-macrophage colony-stimulating factor and sucralfate mouthwashes in the prevention of radiation-induced mucositis: a double-blind prospective randomized phase III study. Int J Radiat Oncol Biol Phys 2002; 54: 479–85.

💊 Preparations

Proprietary Preparations

Arg.: Growgen-GM; Leucomax†; Molcass; Austria: Leucomax†; Belg.: Leucomax†; Braz.: Gramostim†; Leucocitim; Leucomax†; Chile: Leucomax†; Cz.: Leucomax†; Denm.: Leucomax†; Fin.: Leucomax†; Ger.: Leucomax†; Gr.: Leucomax; Mielogen; Hong Kong: Leucomax†; Hung.: Leucomax†; India: Leucomax; Irl.: Leucomax; Israel: Leucomax; Ital.: Leucomax†; Mielogen†; Malaysia: Leucomax†; Mex.: Gramal; Leucomax†; Neth.: Leucomax†; Norw.: Leucomax†; NZ: Leucomax; S.Afr.: Leucomax†; Spain: Leucomax†; Swed.: Leucomax†; Switz.: Leucomax†; Thai.: Leucomax†; UK: Leucomax†; Venez.: Leucomax†.
Published December 11, 2018.