INFORMATION FOR HEALTH PROFESSIONALS
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Active ingredient: molgramostim (recombinant human granulocyte-macrophage colony stimulating factor, non glycosylated, with isoleucine at position 100)
Sterile, lyophilized powder to be reconstituted with a diluent for intravenous (i.v.) or subcutaneous (s.c.) administration, presented in vials containing 300 mcg.
Vials containing powder for injection
Leucomax is indicated
Leucomax must be reconstituted before administration (see `Technical instructions').
Leucomax dosing regimens vary according to the indication for therapy. The maximum daily dose should not exceed 10mcg/kg body weight.
The recommended dosage regimens are:
Cancer chemotherapy
5 to 10mcg/kg per day administered subcutaneously. Treatment should be initiated 24 hours after the last dose of chemotherapy and continued for 7 to 10 days. Dosing may be initiated at 5mcg/kg a day.
Bone marrow transplantation (BMT)
The maximum duration of treatment is 30 days.
Reconstitution of Leucomax - Add 1.0 mL of diluent (bacteriostatic water for injection or sterile water for injection) to the vial of Leucomax. Agitate the vial gently to dissolve the powder completely. This provides the labelled amount of Leucomax as an isotonic solution, which may be used for s.c. administration. When diluted further in accordance with the instructions below, Leucomax may be administered intravenously.
Dilution for i.v. administration - Dilution directions must be followed carefully to avoid loss of molgramostim as a result of adsorption to the infusion system.
Reconstitute each of the required number of vials of lyophilized powder of the appropriate strength of molgramostim with 1 mL of sterile water for injection. The reconstituted molgramostim solution must be further diluted in 25 mL, 50 mL or 100 mL infusion bags or bottles of either normal saline solution or 5% dextrose in water. The number and the strength of lyophilized powder vials required must be such that the above infusion admixture solution contains a final concentration of molgramostim of not less than 7 mcg per mL. The resulting infusion solution is stable for at least 24 hours when stored at refrigeration.
The Travenol I.V. Administration Set 2C0001, Intrafix Air and Infusionsgerät R 87 Plus from Germany, Souplix from France, Travenol C 0334 and Steriflex from United Kingdom, Intravis Air Euroklappe-ISO and Soluset from Spain, and Linfosol Set from Italy are compatible with and may be used to administer these solutions. Significant adsorption of Leucomax has been observed in a Port-A-Cath (Pharmacia) system and its use is not recommended.
Parenteral drug products should be inspected visually for discolouration and particulate matter prior to administration. The reconstituted solution is colourless to light yellow. For i.v. administration, the use of an in-line, low protein binding 0.2 or 0.22 micrometer filter (such as Millipore Durapore) is recommended.
Leucomax is contraindicated in patients with a history of hypersensitivity to molgramostim or any component of the injectable formulation.
Leucomax should not be used in patients with myeloid malignancies.
Leucomax should be used under the supervision of a physician experienced in the treatment of oncologic and haematopoietic disorders or infectious diseases. The first dose of Leucomax should be administered under close medical supervision.
Acute severe, life-threatening hypersensitivity reactions, including anaphylaxis, angio-oedema or bronchoconstriction have occurred in patients receiving Leucomax. If such reactions occur, Leucomax should be withdrawn immediately and not re-introduced.
Leucomax has been associated infrequently with pleuritis, pleural effusion, pericarditis and/or pericardial effusion. If such reactions occur, Leucomax should be withdrawn.
Patients with pre-existing pulmonary disease may be predisposed to decreased pulmonary function and dyspnoea, and should be monitored closely when being treated with Leucomax.
In clinical trials, adverse events reported with initiation of dosing were mostly mild to moderate in severity, and included rigors, dyspnoea, fever, nausea, vomiting, non-specific chest pain, asthenia, hypotension or flushing. These symptoms, which infrequently required withdrawal of Leucomax, were managed symptomatically.
In a few isolated instances, autoimmune disease developed or was exacerbated during rHuGM-CSF therapy; therefore, when administering Leucomax to patients with a history of autoimmune disease, this should be considered.
Standard haematologic tests (complete blood count with differential white blood count and platelet count) should be performed and serum albumin levels monitored during therapy with Leucomax.
Because of the potential of receiving higher doses of chemotherapy (ie., full dose on the prescribed schedule), the patient may be at greater risk of thrombocytopenia and anaemia as consequences of increased chemotherapy doses. Regular monitoring of the platelet count and haematocrit is recommended.
The safety of Leucomax has been demonstrated in a limited number of patients below the age of 18 years.
There are no apparent differences in safety of Leucomax between elderly and non-elderly patients.
Since dosing with Leucomax has been associated with a decrease in serum albumin, drugs that are highly bound to serum albumin may require dosage adjustment.
Although with Leucomax no adverse drug interaction has been reported, the possibility of a drug-drug interaction cannot be excluded completely.
Safety of Leucomax for use in human pregnancy has not been established. Animal studies have shown reproductive toxicity. In primate models, administration of molgramostim was associated with foetal death and spontaneous abortion at doses of 6 and 10mcg/kg a day.
In the absence of clinical data in pregnancy, the therapeutic benefit to the patient must be weighed against potential risks to the progress of pregnancy.
It is not known whether Leucomax is excreted in human milk. However, because of the potential for adverse effects in infants, nursing is not recommended in women receiving Leucomax.
Studies in humans to determine effects of Leucomax on fertility have not been undertaken.
Since many of the undesirable effects reported during Leucomax clinical trials are often associated with underlying or concurrent diseases or their treatment, the causal relationship of these effects to Leucomax cannot be definitively determined. Most adverse reactions observed were mild or moderate in severity. Rarely were they severe or life-threatening.
The most frequently reported undesirable effects across all indications were fever, nausea, dyspnoea, diarrhoea, rash, rigors, injection site reaction (with s.c. administration), vomiting, fatigue, anorexia, musculoskeletal pain and asthenia.
Less frequently reported events include: non-specific chest pain, stomatitis, headache, increased sweating, abdominal pain, pruritus, dizziness, peripheral oedema, paraesthesia and myalgia.
Serious reactions, which occurred rarely in clinical trials, include: anaphylaxis, bronchospasm, cardiac failure, capillary leak syndrome, cerebrovascular disorders, confusion, convulsions, hypotension, cardiac rhythm abnormalities, intracranial hypertension, pericardial effusion, pericarditis, pleural effusion, pulmonary oedema and syncope.
In all patient groups, the most frequently occurring changes in laboratory values were decreased platelet count, decreased haemoglobin level, and decreased serum albumin level. The causal relationship of these changes to Leucomax cannot be determined definitively.
Increased eosinophil counts (absolute and percent) have also been observed.
The frequency of antibodies that bind to molgramostim, measured by enzyme-linked immuno sorbent assay (ELISA) and bioassay, was determined to be 1% post treatment. No loss of activity of Leucomax was evident in these patients.
Accidental overdosing has not been reported with Leucomax. However, in some patients receiving therapeutic doses of 20 or 30mcg/kg per day, tachycardia, hypotension and a flu-like syndrome have been observed; these symptoms abated quickly upon symptomatic treatment
Molgramostim, a recombinant human granulocyte-macrophage colony stimulating factor (rHuGM-CSF), is a water soluble, non-glycosylated protein with isoleucine at position 100. It contains 127 amino acids and has a molecular weight of 14,477 daltons. Molgramostim is produced by a strain of Escherichia coli bearing a genetically engineered plasmid which contains a human GM-CSF gene.
Being a multi-lineage glycoprotein regulator involved in both the regulation of haematopoiesis and the activation of mature myeloid cells, molgramostim stimulates in vitro the proliferation and differentiation of haematopoietic precursor cells resulting in the production of granulocytes, monocytes/macrophages and T-lymphocytes.
Studies on fresh tumour explants in the human tumour clonogenic assay have demonstrated that molgramostim neither stimulates nor inhibits tumour cell growth. rHuGM-CSF can enhance expression of major histocompatibility class II antigens on human monocytes and can augment antibody production. In addition, rHuGM-CSF exhibits marked effects on the functional activity of mature neutrophils, including enhanced phagocytosis of bacteria, enhanced cytotoxicity toward malignant cells and priming of neutrophils for enhanced oxidative metabolism, an important reaction related to host defense.
In vivo studies performed in cynomolgus monkeys demonstrated that the intravenous or subcutaneous bolus administration of molgramostim results in significant increases in the white blood cell (WBC) count. Serial differential counts indicate that this increase mainly concerns the neutrophilic granulocytes and, to a lesser extent, the lymphocytes and eosinophils. In a study of the kinetics of response, the effect of a single dose of molgramostim usually appeared within 1 to 4 hours and reached its peak within 6 to 18 hours after initiation of dosing. Results of a dose-response study in cynomolgus monkeys utilising i.v. bolus injections of molgramostim for 5 consecutive days indicate that maximal response can be achieved at 15mcg/kg a day. Molgramostim has also been shown to increase the WBC count in a leucopenic cynomolgus monkey treated previously with cyclophosphamide.
Studies in rats showed that radioactivity was extensively distributed following i.v. administration of 125I-rHuGM-CSF. The drug appeared to be rapidly metabolised and excreted. The pharmacokinetic profiles of molgramostim were similar in monkeys, healthy male volunteers and patients. After s.c. doses of 3, 10 or 20mcg/kg and after i.v. doses of 3 to 30 mcg/kg, increases in the total area under curve (AUC) were dose-related. Maximum molgramostim serum concentrations were reached in 3 to 4 hours after s.c. administration. Molgramostim had an elimination half-life of 1 to 2 hours after i.v. administration and of 2 to 3 hours after s.c. administration. The slightly longer half-life observed after s.c. administration is probably due to prolonged absorption from the injection site.
In long-term studies (up to 1 year) in rats and dogs no marked toxic effects were seen in either species up to oral doses of about 100 mg/kg a day. At high oral doses, the liver and possibly also the kidneys were identified as potential target organs.
In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings attributable to treatment were made up to doses of 130 (males) and 156 (females) mg/kg a day. In a two-year oral carcinogenicity study in rats, an increased incidence of liver tumours was observed in males at the highest dose level of 69 mg/kg a day. The changes which may be associated with peroxisome proliferation have been shown to be species-specific since they were not seen in the carcinogenicity study in mice or in other studies in mice, dogs or monkeys.
During high-dose studies in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level 50 mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after drug discontinuation. They were not associated with histological changes.
A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of mutagenic or clastogenic potential.
No adverse effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.
None known.
Inactive ingredients: mannitol, citric acid, anhydrous, diabasic sodium phosphate, polyethylene glycol (macrogol 4000); human albumin.
Leucomax sterile powder, packaged in a Type-I glass vial with butyl or halobutyl rubber closure and aluminium seal, is stable for 24 months when stored at 2 to 8°C and protected from light.
Refrigerate do not freeze.
After reconstitution with bacteriostatic water for injection, Leucomax solution can be used for 1 week when stored at 2 to 8°C, or the solution may be frozen and is then stable for 28 days. The frozen product may be allowed to thaw and refreeze no more than twice.
After reconstitution with sterile water for injection, Leucomax solution can be used for 24 hours when refrigerated at 2 to 8°C. Unused Leucomax solution should be discarded
Protect from light.
Boxes containing 1 vial of Leucomax and 1 vial diluent (Water for Injection)
Vials containing 300mcg of molgramostim
Prescription Medicine
Schering-Plough Pty Ltd
33 Whakatiki Street
Private Bag 908
Upper Hutt
WELLINGTON
Telephone: 0800 468 766
6 November 2002
(Ref: BPI 23/10/92)