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Aspirin Lysine (BANM) is known as Aspirin in the US.
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Glossary
| BANM | British Approved Name (Modified) |
Cyclin may be available in the countries listed below.
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In the US, Methyldopa (methyldopa systemic) is a member of the drug class antiadrenergic agents, centrally acting and is used to treat High Blood Pressure and Hypertensive Emergency.
US matches:
UK matches:
Rec.INN
0000555-30-6
C10-H13-N-O4
211
Antihypertensive agent
L-Tyrosine, 3-hydroxy-α-methyl-
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Glossary
| BAN | British Approved Name |
| DCF | Dénomination Commune Française |
| DCIT | Denominazione Comune Italiana |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Mucolator may be available in the countries listed below.
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Xamiol 50 micrograms/g + 0.5 mg/g gel
One gram of gel contains 50 micrograms of calcipotriol (as monohydrate) and 0.5 mg of betamethasone (as dipropionate).
Excipient: 160 micrograms butylated hydroxytoluene/g gel.
For a full list of excipients, see section 6.1.
Gel.
An almost clear, colourless to slightly off-white gel.
Topical treatment of scalp psoriasis in adults.
Posology
Xamiol gel should be applied to affected areas once daily. The recommended treatment period is 4 weeks. If it is necessary to continue or restart treatment after this period, treatment should be continued after medical review and under regular medical supervision.
When using calcipotriol containing medicinal products, the maximum daily dose should not exceed 15 g. The body surface area treated with calcipotriol containing medicinal products should not exceed 30% (see section 4.4).
All the affected scalp areas may be treated with Xamiol gel. Usually an amount between 1 g and 4 g per day is sufficient for treatment of the scalp (4g corresponds to one teaspoon).
Special populations
Renal and hepatic impairment
The safety and efficacy of Xamiol gel in patients with severe renal insufficiency or severe hepatic disorders have not been evaluated.
Paediatric population
The safety and efficacy of Xamiol gel in children below 18 years have not been established. No data are available.
Method of administration
The bottle should be shaken before use and Xamiol gel applied to the affected area. Xamiol gel should not be applied directly to the face or eyes. The hands should be washed after use. In order to achieve optimal effect, it is not recommended to wash the hair immediately after application of Xamiol gel. Xamiol gel should remain on the scalp during the night or during the day.
Hypersensitivity to the active substances or to any of the excipients.
Xamiol gel is contraindicated in erythrodermic, exfoliative and pustular psoriasis.
Due to the content of calcipotriol, Xamiol gel is contraindicated in patients with known disorders of calcium metabolism.
Due to the content of corticosteroid, Xamiol gel is contraindicated in the following conditions: Viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers, wounds, perianal and genital pruritus.
Effects on endocrine system
Xamiol gel contains a potent group III steroid and concurrent treatment with other steroids on the scalp must be avoided. Adverse reactions found in connection with systemic corticosteroid treatment, such as adrenocortical suppression or impact on the metabolic control of diabetes mellitus, may occur also during topical corticosteroid treatment due to systemic absorption. Application under occlusive dressings should be avoided since it increases the systemic absorption of corticosteroids. Application on large areas of damaged skin or on mucous membranes or in skin folds should be avoided since it increases the systemic absorption of corticosteroids (see section 4.8).
In a study in patients with both extensive scalp and extensive body psoriasis using a combination of high doses of Xamiol gel (scalp application) and high doses of Dovobet ointment (body application), 5 of 32 patients showed a borderline decrease in cortisol response to adrenocorticotropic hormone (ACTH) challenge after 4 weeks of treatment (see section 5.1).
Effects on calcium metabolism
Due to the content of calcipotriol, hypercalcaemia may occur if the maximum daily dose (15 g) is exceeded. Serum calcium is, however, quickly normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are followed.
Treatment of more than 30% of the body surface should be avoided (see section 4.2).
Local adverse reactions
Skin of the face and genitals are very sensitive to corticosteroids. The medicinal product should not be used in these areas. Uncommon local adverse reactions (such as eye irritation or irritation of facial skin) were observed, when the medicinal product was accidentally administered in the area of face, or accidentally to the eyes or conjunctives (see sections 4.8 and 5.1). The patient must be instructed in correct use of the medicinal product to avoid application and accidental transfer to the face, mouth and eyes. Hands must be washed after each application to avoid accidental transfer to these areas.
Concomitant skin infections
When lesions become secondarily infected, they should be treated with antimicrobiological therapy. However, if infection worsens, treatment with corticosteroids should be stopped.
Discontinuation of treatment
When treating psoriasis with topical corticosteroids, there may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing treatment. Medical supervision should therefore continue in the post-treatment period.
Long-term use
With long-term use there is an increased risk of local and systemic corticosteroid adverse reactions. The treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroid (see section 4.8).
Unevaluated uses
There is no experience for the use of Xamiol gel in guttate psoriasis.
Concurrent treatment and UV exposure
Dovobet ointment for body psoriasis lesions has been used in combination with Xamiol gel for scalp psoriasis lesions, but there is no experience of combination of Xamiol with other topical anti-psoriatic products at the same treatment area, other anti-psoriatic medicinal products administered systemically or with phototherapy.
During Xamiol gel treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks (see section 5.3).
Adverse reactions to excipients
Xamiol gel contains butylated hydroxytoluene (E321), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.
No interaction studies have been performed.
Pregnancy
There are no adequate data from the use of Xamiol gel in pregnant women. Studies in animals with glucocorticoids have shown reproductive toxicity (see section 5.3), but a number of epidemiological studies have not revealed congenital anomalies among infants born to women treated with corticosteroids during pregnancy. The potential risk for humans is uncertain. Therefore, during pregnancy, Xamiol gel should only be used when the potential benefit justifies the potential risk.
Breastfeeding
Betamethasone passes into breast milk, but risk of an adverse effect on the infant seems unlikely with therapeutic doses. There are no data on the excretion of calcipotriol in breast milk. Caution should be exercised when prescribing Xamiol gel to women who breast-feed.
Fertility
Studies in rats with oral doses of calcipotriol or betamethasone dipropionate demonstrated no impairment of male and female fertility
Xamiol gel has no influence on the ability to drive and use machines.
The clinical trial programme for Xamiol gel has so far included more than 4,400 patients of whom more than 1,900 were treated with Xamiol gel. Approximately 8% of patients treated with Xamiol gel experienced a non-serious adverse reaction.
These reactions are usually mild and cover mainly various skin reactions with pruritus being the most common.
Based on data from clinical trials and postmarket use the following adverse reactions are listed for Xamiol gel.
The adverse reactions are listed by MedDRA System Organ Class, and the individual adverse reactions are listed starting with the most frequently reported. Within each frequency grouping, the adverse reactions are listed in order of decreasing seriousness.
The following terminologies have been used in order to classify the frequencies of adverse reactions:
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Not known (cannot be estimated from the available data)
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The following adverse reactions are considered to be related to the pharmacological classes of calcipotriol and betamethasone, respectively:
Calcipotriol
Adverse reactions include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity and hypersensitivity reactions including very rare cases of angioedema and facial oedema. Systemic effects after topical use may appear very rarely causing hypercalcaemia or hypercalciuria (see section 4.4).
Betamethasone (as dipropionate)
Local reactions can occur after topical use, especially during prolonged application, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating psoriasis, there may be a risk of generalised pustular psoriasis.
Systemic reactions due to topical use of corticosteroids are rare in adults, however they can be severe. Adrenocortical suppression, cataract, infections, impact on the metabolic control of diabetes mellitus and increase of intra-ocular pressure can occur, especially after long-term treatment. Systemic reactions occur more frequently when applied under occlusion (plastic, skin folds), when applied on large areas and during long-term treatment (see section 4.4).
Use above the recommended dose may cause elevated serum calcium which should rapidly subside when treatment is discontinued.
Excessive prolonged use of topical corticosteroids may suppress the pituitary-adrenal functions, resulting in secondary adrenal insufficiency which is usually reversible. In such cases, symptomatic treatment is indicated.
In case of chronic toxicity, the corticosteroid treatment must be discontinued gradually.
It has been reported that due to misuse one patient with extensive erythrodermic psoriasis treated with 240 g of Dovobet ointment weekly (corresponding to a daily dose of approximately 34g) for 5 months (maximum recommended dose 15g daily) developed Cushing's syndrome and pustular psoriasis after abruptly stopping treatment.
Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, Calcipotriol, combinations.
ATC Code: D05AX52
Calcipotriol is a vitamin D analogue. In vitro data suggest that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.
Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppresive properties, however, without curing the underlying condition. Through occlusion the effect can be enhanced due to increased penetration of the stratum corneum. The incidence of adverse events will increase because of this. In general, the mechanism of the anti-inflammatory activity of the topical steroids is unclear.
Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both extensive scalp and body psoriasis, using up to 106 g per week combined Xamiol gel and Dovobet ointment. A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of 32 patients (15.6%) after 4 weeks of treatment and in 2 of 11 patients (18.2%) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of change of calcium metabolism observed in these patients. With regard to HPA suppression, therefore, this study shows some evidence that very high doses of Xamiol gel and Dovobet ointment may have a weak effect on the HPA axis.
The efficacy of once daily use of Xamiol gel was investigated in two randomised, double-blind, 8-week clinical studies including a total of more than 2,900 patients with scalp psoriasis of at least mild severity according to the Investigator's Global Assessment of disease severity (IGA). Comparators were betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and (in one of the studies) the gel vehicle alone, all used once daily. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that Xamiol gel was statistically significantly more effective than the comparators. Results for speed of onset based on similar data at week 2 also showed Xamiol gel to be statistically significantly more effective than the comparators.
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1 Statistically significantly less effective than Xamiol gel (P<0.001)
Another randomised, investigator-blinded clinical study including 312 patients with scalp psoriasis of at least moderate severity according to the IGA investigated use of Xamiol gel once daily compared with Dovonex Scalp solution twice daily for up to 8 weeks. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that Xamiol gel was statistically significantly more effective than Dovonex Scalp solution.
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1 Statistically significantly less effective than Xamiol gel (P<0.001)
A randomised, double-blind long-term clinical study including 873 patients with scalp psoriasis of at least moderate severity (according to the IGA) investigated the use of Xamiol gel compared with calcipotriol in the gel vehicle. Both treatments were applied once daily, intermittently as required, for up to 52 weeks. Adverse events possibly related to long-term use of corticosteroids on the scalp, were identified by an independent, blinded panel of dermatologists. There was no difference in the percentages of patients experiencing such adverse events between the treatment groups (2.6% in the Xamiol gel group and 3.0% in the calcipotriol group; P=0.73). No cases of skin atrophy were reported.
The systemic exposure to calcipotriol and betamethasone dipropionate from topically applied Xamiol gel is comparable to Dovobet ointment in rats and minipigs. Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Dovobet ointment formulation is less than 1% of the dose (2.5 g) when applied to normal skin (625 cm2) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids. Absorption through damaged skin is approx. 24 %.
Following systemic exposure, both active ingredients – calcipotriol and betamethasone dipropionate – are rapidly and extensively metabolised. Protein binding is approx. 64 %. Plasma elimination half-life after intravenous application is 5-6 hours. Due to the formation of a depot in the skin elimination after dermal application is in order of days. Betamethasone is metabolised especially in the liver, but also in the kidneys to glucuronide and sulphate esters. The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate, respectively, showed that the kidney and liver had the highest level of radioactivity.
Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples of 34 patients treated for 4 or 8 weeks with both Xamiol gel and Dovobet ointment for extensive psoriasis involving the body and scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients.
Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction toxicity studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour were detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility. The relevance for humans is unknown.
A dermal carcinogenicity study with calcipotriol in mice revealed no special hazard to humans.
Photo(co)carcinogenicity studies in mice suggest that calcipotriol may enhance the effect of UVR to induce skin tumours.
No carcinogenicity or photocarcinogenicity studies have been performed with betamethasone dipropionate.
In local tolerability studies in rabbits, Xamiol gel caused mild to moderate skin irritation and a slight transient irritation of the eye.
Paraffin, liquid
Polyoxypropylene-15 stearyl ether
Castor oil, hydrogenated
Butylhydroxytoluene (E321)
All-rac-α-tocopherol
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
2 years.
After first opening: 3 months.
Do not refrigerate. Keep the bottle in the outer carton in order to protect from light.
High-density polyethylene bottles with low-density polyethylene nozzle and a high-density polyethylene screw cap. The bottles are placed in cartons.
Pack sizes: 15, 30, 60 and 2 x 60 g.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
LEO Pharmaceutical Products Ltd. A/S
Industriparken 55
DK-2750 Ballerup
Denmark
PL 05293/0006
25/09/2008
11/03/2011
Thado may be available in the countries listed below.
Thalidomide is reported as an ingredient of Thado in the following countries:
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Cefazid may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Cefalexin monohydrate (a derivative of Cefalexin) is reported as an ingredient of Cefazid in the following countries:
Ceftazidime is reported as an ingredient of Cefazid in the following countries:
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Fenoprofen Calcium (BANM, JAN, USAN) is known as Fenoprofen in the US.
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Glossary
| BANM | British Approved Name (Modified) |
| JAN | Japanese Accepted Name |
| USAN | United States Adopted Name |
Ranacox may be available in the countries listed below.
Etoricoxib is reported as an ingredient of Ranacox in the following countries:
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Ratiograstim 48 MIU/0.8 ml solution for injection or infusion
Each ml of solution for injection or infusion contains 60 million international units [MIU] (600 µg) of filgrastim.
Each pre-filled syringe contains 48 MIU (480 µg) of filgrastim in 0.8 ml solution for injection or infusion.
Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced in Escherichia coli K802 by recombinant DNA technology.
Excipient: Each ml of solution contains 50 mg of sorbitol.
For a full list of excipients, see section 6.1.
Solution for injection or infusion
Clear, colourless solution.
Ratiograstim is indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) and for the reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia. The safety and efficacy of filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
Ratiograstim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC).
In patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia with an absolute neutrophil count (ANC) of 9/l, and a history of severe or recurrent infections, long term administration of Ratiograstim is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
Ratiograstim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 x 109/l) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate.
Special requirements
Filgrastim therapy should only be given in collaboration with an oncology centre which has experience in granulocyte-colony stimulating factor (G
Established cytotoxic chemotherapy
The recommended dose of filgrastim is 0.5 MIU (5 μg)/kg/day. The first dose of filgrastim should not be administered less than 24 hours following cytotoxic chemotherapy. Filgrastim may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in glucose 50 mg/ml (5%) solution for infusion given over 30 minutes (see section 6.6 for instructions on dilution).
The subcutaneous route is preferred in most cases. There is some evidence from a study of single dose administration that intravenous dosing may shorten the duration of effect. The clinical relevance of this finding to multiple dose administration is not clear. The choice of route should depend on the individual clinical circumstance. In randomised clinical trials, a subcutaneous dose of 23 MIU (230 μg)/m2/day (4.0 to 8.4 μg/kg/day) was used.
Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Following established chemotherapy for solid tumours, lymphomas and lymphoid leukaemias, it is expected that the duration of treatment required to fulfil these criteria will be up to 14 days. Following induction and consolidation treatment for acute myeloid leukaemia the duration of treatment may be substantially longer (up to 38 days) depending on the type, dose and schedule of cytotoxic chemotherapy used.
In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim therapy should not be discontinued before the expected nadir has passed and the neutrophil count has recovered to the normal range. Premature discontinuation of filgrastim therapy prior to the time of the expected neutrophil nadir is not recommended.
In patients treated with myeloablative therapy followed by bone marrow transplantation
The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/kg/day given as a 30 minute or 24 hour intravenous infusion or 1.0 MIU (10 μg)/kg/day given by continuous 24 hour subcutaneous infusion. Filgrastim should be diluted in 20 ml of glucose 50 mg/ml (5%) solution for infusion (see section 6.6 for instructions on dilution).
The first dose of filgrastim should not be administered less than 24 hours following cytotoxic chemotherapy and within 24 hours of bone marrow infusion.
Once the neutrophil nadir has been passed the daily dose of filgrastim should be titrated against the neutrophil response as follows:
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For the mobilisation of PBPC in patients undergoing myelosuppressive or myeloablative therapy followed by autologous peripheral blood progenitor cell transplantation
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MIU (10 μg)/kg/day as a 24 hour subcutaneous continuous infusion or a single daily subcutaneous injection for 5 to 7 consecutive days. For infusions, filgrastim should be diluted in 20 ml of glucose 50 mg/ml (5%) solution for infusion (see section 6.6 for instructions on dilution). Timing of leukapheresis: 1 or 2 leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukaphereses may be necessary. Filgrastim dosing should be maintained until the last leukapheresis.
The recommended dose of filgrastim for PBPC mobilisation after myelosuppressive chemotherapy is 0.5 MIU (5 μg)/kg/day given daily by subcutaneous injection from the first day after completion of chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Leukapheresis should be performed during the period when the ANC rises from < 0.5 x 109/l to> 5.0 x 109/l. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended.
For the mobilisation of PBPC in normal donors prior to allogeneic peripheral blood progenitor cell transplantation
For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU (10 μg)/kg/day subcutaneously for 4 to 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if needed in order to collect 4 x 106 CD34+ cells/kg recipient bodyweight.
In patients with severe chronic neutropenia (SCN)
Congenital neutropenia
The recommended starting dose is 1.2 MIU (12 μg)/kg/day subcutaneously as a single dose or in divided doses.
Idiopathic or cyclic neutropenia
The recommended starting dose is 0.5 MIU (5 μg)/kg/day subcutaneously as a single dose or in divided doses.
Dose adjustment
Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has reached and can be maintained at more than 1.5 x 109/l. When the response has been obtained, the minimal effective dose to maintain this level should be established. Long-term daily administration is required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose may be doubled or halved depending upon the patient's response. Subsequently the dose may be individually adjusted every 1 to 2 weeks to maintain the average neutrophil count between 1.5 x 109/l and 10 x 109/l. A faster schedule of dose escalation may be considered in patients presenting with severe infections. In clinical trials, 97% of patients who responded had a complete response at doses of 2.4 MIU (24 μg)/kg/day. The long-term safety of filgrastim administration above 2.4 MIU (24 μg)/kg/day in patients with SCN has not been established.
In patients with HIV infection
For reversal of neutropenia
The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day given daily by subcutaneous injection with titration up to a maximum of 0.4 MIU (4 μg)/kg/day until a normal neutrophil count is reached and can be maintained (ANC> 2.0 x109/l). In clinical studies,> 90% of patients responded at these doses, achieving reversal of neutropenia in a median of 2 days.
In a small number of patients (< 10%), doses up to 1.0 MIU (10 μg)/kg/day were required to achieve reversal of neutropenia.
For maintaining normal neutrophil counts
When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MIU (300 μg)/day by subcutaneous injection is recommended. Further dose adjustment may be necessary, as determined by the patient's ANC, to maintain the neutrophil count at> 2.0 x 109/l. In clinical studies, dosing with 30 MIU (300 μg)/day on 1 to 7 days per week was required to maintain the ANC> 2.0 x 109/l, with the median dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC> 2.0 x 109/l.
Special populations
Elderly patients
Clinical trials with filgrastim have included a small number of elderly patients but special studies have not been performed in this group and therefore specific dosage recommendations cannot be made.
Patients with renal or hepatic impairment
Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. Dose adjustment is not required in these circumstances.
Paediatric use in the SCN and cancer settings
Sixty-five percent of the patients studied in the SCN trial programme were under 18 years of age. The efficacy of treatment was clear for this age group, which included most patients with congenital neutropenia. There were no differences in the safety profiles for paediatric patients treated for severe chronic neutropenia.
Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are similar in both adults and children receiving cytotoxic chemotherapy.
The dosage recommendations in paediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy.
Hypersensitivity to the active substance or to any of the excipients.
Special warnings
Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens (see below).
Filgrastim should not be administered to patients with severe congenital neutropenia (Kostman's syndrome) with abnormal cytogenetics (see below).
Special precautions in patients with acute myeloid leukaemia
Malignant cell growth
Granulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects may also be seen on some non-myeloid cells in vitro.
The safety and efficacy of filgrastim administration in patients with myelodysplastic syndrome or chronic myelogenous leukaemia have not been established. Therefore, filgrastim is not indicated for use in these conditions. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia.
In view of limited safety and efficacy data in patients with secondary AML, filgrastim should be administered with caution.
The safety and efficacy of filgrastim administration in de novo AML patients aged < 55 years with good cytogenetics [t(8;21), t(15;17), and inv(16)] have not been established.
Other special precautions
Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with filgrastim for more than 6 months.
Rare pulmonary undesirable effects, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. The onset of pulmonary signs such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of Adult Respiratory Distress Syndrome (ARDS). Filgrastim should be discontinued and appropriate treatment given in these cases.
Special precautions in cancer patients
Leukocytosis
White blood cell counts of 100 x 109/l or greater have been observed in less than 5% of patients receiving filgrastim at doses above 0.3 MIU/kg/day (3 μg/kg/day). No undesirable effects directly attributable to this degree of leukocytosis have been reported. However, in view of the potential risks associated with severe leukocytosis, a white blood cell count should be performed at regular intervals during filgrastim therapy. If leukocyte counts exceed 50 x 109/l after the expected nadir, filgrastim should be discontinued immediately. However, during the period of administration of filgrastim for PBPC mobilisation, filgrastim should be discontinued or its dosage should be reduced if the leukocyte counts rise to> 70 x 109/l.
Risks associated with increased doses of chemotherapy
Special caution should be used when treating patients with high dose chemotherapy because improved tumour outcome has not been demonstrated and intensified doses of chemotherapeutic agents may lead to increased toxicities including cardiac, pulmonary, neurologic and dermatologic effects (please refer to the Summary of Product Characteristics of the specific chemotherapy agents used).
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive chemotherapy. Because of the potential of receiving higher doses of chemotherapy (e.g. full doses on the prescribed schedule) the patient may be at greater risk of thrombocytopenia and anaemia. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.
The use of filgrastim-mobilised PBPCs has been shown to reduce the depth and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.
Other special precautions
The effects of filgrastim in patients with substantially reduced myeloid progenitors have not been studied. Filgrastim acts primarily on neutrophil precursors to exert its effect in elevating neutrophil counts. Therefore, in patients with reduced precursors, neutrophil response may be diminished (such as those treated with extensive radiotherapy or chemotherapy, or those with bone marrow infiltration by tumour).
The effect of filgrastim on graft versus host disease has not been defined.
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging findings. This should be considered when interpreting bone-imaging results.
Special precautions in patients undergoing peripheral blood progenitor cell mobilisation
Mobilisation
There are no prospectively randomised comparisons of the two recommended mobilisation methods (filgrastim alone or in combination with myelosuppressive chemotherapy) within the same patient population. The degree of variation between individual patients and between laboratory assays of CD34+ cells mean that direct comparison between different studies is difficult. It is therefore difficult to recommend an optimum method. The choice of mobilisation method should be considered in relation to the overall objectives of treatment for an individual patient.
Prior exposure to cytotoxic agents
Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient mobilisation of PBPC to achieve the recommended minimum yield (2.0 x 106 CD34+ cells/kg) or acceleration of platelet recovery to the same degree.
Some cytotoxic agents exhibit particular toxicities to the haematopoietic progenitor pool and may adversely affect progenitor mobilisation. Agents such as melphalan, carmustine (BCNU) and carboplatin, when administered over prolonged periods prior to attempts at progenitor mobilisation, may reduce progenitor yield. However, the administration of melphalan, carboplatin or BCNU together with filgrastim has been shown to be effective for progenitor mobilisation. When a peripheral blood progenitor cell transplantation is envisaged it is advisable to plan the stem cell mobilisation procedure early in the treatment course of the patient. Particular attention should be paid to the number of progenitors mobilised in such patients before the administration of high-dose chemotherapy. If yields are inadequate, as measured by the criteria above, alternative forms of treatment not requiring progenitor support should be considered.
Assessment of progenitor cell yields
In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular attention should be paid to the method of quantitation. The results of flow cytometric analysis of CD34+ cell numbers vary depending on the precise methodology used and therefore, recommendations of numbers based on studies in other laboratories need to be interpreted with caution.
Statistical analysis of the relationship between the number of CD34+ cells re-infused and the rate of platelet recovery after high-dose chemotherapy indicates a complex but continuous relationship.
The recommendation of a minimum yield of 2.0 x 106 CD34+ cells/kg is based on published experience resulting in adequate haematologic reconstitution. Yields in excess of this minimum yield appear to correlate with more rapid recovery, those below with slower recovery.
Special precautions in normal donors undergoing peripheral blood progenitor cell mobilisation
Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be considered for the purposes of allogeneic stem cell transplantation.
PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory eligibility criteria for stem cell donation. Particular attention should be paid to haematological values and infectious diseases.
The safety and efficacy of filgrastim have not been assessed in normal donors < 16 years or> 60 years.
Transient thrombocytopenia (platelets < 100 x 109/l) following filgrastim administration and leukapheresis was observed in 35% of subjects studied. Among these, two cases of platelets < 50 x 109/l were reported and attributed to the leukapheresis procedure.
If more than one leukapheresis is required, particular attention should be paid to donors with platelets < 100 x 109/l prior to leukapheresis; in general apheresis should not be performed if platelets < 75 x 109/l.
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects in haemostasis.
Filgrastim administration should be discontinued or its dosage should be reduced if the leukocyte counts rise to> 70 x109/l.
Donors who receive G-CSFs for PBPC mobilisation should be monitored until haematological indices return to normal.
Transient cytogenic modifications have been observed in normal donors following G-CSF use. The significance of these changes in terms of the development of haematological malignancy is unknown. Long-term safety follow-up of donors is ongoing. A risk of promotion of a malignant myeloid clone can not be excluded. It is recommended that the apheresis centre perform a systematic record and tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been reported in healthy donors and patients following administration of G-CSFs. Some cases of splenic rupture were fatal. Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in donors and/or patients reporting left upper abdominal pain or shoulder tip pain.
Special precautions in recipients of allogeneic PBPC mobilised with filgrastim
Current data indicate that immunological interactions between the allogeneic PBPC graft and the recipient may be associated with an increased risk of acute and chronic graft versus host disease when compared with bone marrow transplantation.
Special precautions in SCN patients
Blood cell counts
Platelet counts should be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be given to intermittent cessation or decreasing the dose of filgrastim in patients who develop thrombocytopenia, i.e. platelets consistently < 100,000/mm3.
Other blood cell changes occur, including anaemia and transient increases in myeloid progenitors, which require close monitoring of cell counts.
Transformation to leukaemia or myelodysplastic syndrome
Special care should be taken in the diagnosis of severe chronic neutropenias to distinguish them from other haematopoietic disorders such as aplastic anaemia, myelodysplasia and myeloid leukaemia. Complete blood cell counts with differential and platelet counts and an evaluation of bone marrow morphology and karyotype should be performed prior to treatment.
There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukaemia in clinical trial patients with SCN treated with filgrastim. This observation has only been made in patients with congenital neutropenia. MDS and leukaemias are natural complications of the disease and are of uncertain relation to filgrastim therapy. A subset of approximately 12% of patients who had normal cytogenetic evaluations at baseline were subsequently found to have abnormalities, including monosomy 7, on routine repeat evaluation. If patients with SCN develop abnormal cytogenetics, the risks and benefits of continuing filgrastim should be carefully weighed; filgrastim should be discontinued if MDS or leukaemia occur. It is currently unclear whether long-term treatment of patients with SCN will predispose patients to cytogenetic abnormalities, MDS or leukaemic transformation. It is recommended to perform morphologic and cytogenetic bone marrow examinations in patients at regular intervals (approximately every 12 months).
Other special precautions
Causes of transient neutropenia such as viral infections should be excluded.
Splenic enlargement is a direct effect of treatment with filgrastim. Thirty-one percent (31%) of patients in studies were documented as having palpable splenomegaly. Increases in volume, measured radiographically, occurred early during filgrastim therapy and tended to plateau. Dose reductions were noted to slow or stop the progression of splenic enlargement and in 3% of patients a splenectomy was required. Spleen size should be evaluated regularly. Abdominal palpation should be sufficient to detect abnormal increases in splenic volume.
Haematuria/proteinuria occurred in a small number of patients. Regular urinanalysis should be performed to monitor this event.
The safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.
Special precautions in patients with HIV infection
Blood cell counts
ANC should be monitored closely, especially during the first few weeks of filgrastim therapy. Some patients may respond very rapidly and with a considerable increase in neutrophil count to the initial dose of filgrastim. It is recommended that the ANC is measured daily for the first 2 to 3 days of filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice weekly for the first two weeks and subsequently once per week or once every other week during maintenance therapy. During intermittent dosing with 30 MIU (300 μg)/day of filgrastim, there can be wide fluctuations in the patient's ANC over time. In order to determine a patient's trough or nadir ANC, it is recommended that blood samples are taken for ANC measurement immediately prior to any scheduled dosing with filgrastim.
Risk associated with increased doses of myelosuppressive medicinal products
Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive medicinal products. As a result of the potential to receive higher doses or a greater number of these medicinal products with filgrastim therapy, the patient may be at higher risk of developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see above).
Infections and malignancies causing myelosuppression
Neutropenia may be due to bone marrow infiltrating opportunistic infections such as Mycobacterium avium complex or malignancies such as lymphoma. In patients with known bone marrow-infiltrating infections or malignancy, consider appropriate therapy for treatment of the underlying condition in addition to administration of filgrastim for treatment of neutropenia. The effects of filgrastim on neutropenia due to bone marrow-infiltrating infection or malignancy have not been well established.
Special precautions in sickle cell disease
Sickle cells crises, in some cases fatal, have been reported with the use of filgrastim in subjects with sickle cell disease. Physicians should exercise caution when considering the use of filgrastim in patients with sickle cell disease and only after careful evaluation of the potential risks and benefits.
Excipients
Ratiograstim contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not use this medicinal product.
The safety and efficacy of filgrastim given on the same day as myelosuppressive cytotoxic chemotherapy have not been definitively established. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, the use of filgrastim is not recommended in the period from 24 hours before to 24 hours after chemotherapy. Preliminary evidence from a small number of patients treated concomitantly with filgrastim and 5-Fluorouracil indicates that the severity of neutropenia may be exacerbated.
Possible interactions with other haematopoietic growth factors and cytokines have not yet been investigated in clinical trials.
Since lithium promotes the release of neutrophils, it is likely to potentiate the effect of filgrastim. Although this interaction has not been formally investigated, there is no evidence that such an interaction is harmful.
There are no adequate data from the use of filgrastim in pregnant women. There are reports in the literature where the transplacental passage of filgrastim in pregnant women has been demonstrated. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Filgrastim should not be used during pregnancy unless clearly necessary.
It is unknown whether filgrastim is excreted in human breast milk. The excretion of filgrastim in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with filgrastim should be made taking into account the benefit of breast-feeding to the child and the benefit of filgrastim therapy to the woman.
Filgrastim has minor or moderate influence on the ability to drive and use machines. If the patient is experiencing fatigue, caution is advised when driving a car or operating machinery.
During clinical studies 541 cancer patients and 188 healthy volunteers were exposed to Ratiograstim. The safety profile of Ratiograstim observed in these clinical studies was consistent with that reported with the reference product used in these studies.
The following undesirable effects and their frequencies have been observed under treatment with filgrastim based on published information.
The assessment of undesirable effects is based on the following frequency data:
Very common:
Common: | |
Uncommon: | |
Rare: | |
Very rare: | <1/10,000 |
Not known: | cannot be estimated from the available data |
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
In cancer patients
In clinical trials, the most frequent undesirable effects attributable to filgrastim at the recommended dose were mild or moderate musculoskeletal pain, occurring in 10%, and severe musculoskeletal pain in 3% of patients. Musculoskeletal pain is usually controlled with standard analgesics. Less frequent undesirable effects include urinary abnormalities predominantly mild or moderate dysuria.
In randomised, placebo-controlled clinical trials, filgrastim did not increase the incidence of undesirable effects associated with cytotoxic chemotherapy. Undesirable effects reported with equal frequency in patients treated with filgrastim/chemotherapy and placebo/chemotherapy included nausea and vomiting, alopecia, diarrhoea, fatigue, anorexia, mucositis, headache, cough, skin rash, chest pain, generalised weakness, sore throat, constipation and unspecified pain.
Reversible, dose-dependent and usually mild or moderate elevations of lactate dehydrogenase (LDH), alkaline phosphatase, serum uric acid and gamma-glutamyltransferase (GGT) occurred with filgrastim in approximately 50%, 35%, 25%, and 10% of patients respectively, at recommended doses.
Transient decreases in blood pressure, not requiring clinical treatment, have been reported occasionally.
Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been reported occasionally in patients undergoing high dose chemotherapy followed by autologous bone marrow transplantation. The causal association with filgrastim has not been established.
Very rare events of cutaneous vasculitis have been reported in patients treated with filgrastim. The mechanism of vasculitis in patients receiving filgrastim is unknown.
The occurrence of Sweet's syndrome (acute febrile dermatosis) has been reported occasionally. However, since a significant percentage of these patients were suffering from leukaemia, a condition known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been established.
Exacerbation of rheumatoid arthritis has been observed in individual cases.
Rare pulmonary undesirable effects including interstitial pneumonia, pulmonary oedema and pulmonary infiltrates have been reported in some cases with an outcome of respiratory failure or adult respiratory distress syndrome (ARDS) which may be fatal (see section 4.4).
Allergic Reactions: Allergic-type reactions, including anaphylaxis, skin rash, urticaria, angioedema, dyspnoea and hypotension, occurring on initial or subsequent treatment, have been reported in patients receiving filgrastim. Overall, reports were more common after IV administration. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be permanently discontinued in patients who experience a serious allergic reaction.
Isolated cases of sickle cells crises have been reported in patients with sickle cell disease (see section 4.4).
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In peripheral blood progenitor cell mobilisation in normal donors
The most commonly reported undesirable effect was mild to moderate transient musculo-skeletal pain. Leukocytosis (WBC> 50 x 109/l) was observed in 41% of donors and transient thrombocytopenia (platelets < 100 x 109/l) following filgrastim and leukapheresis was observed in 35% of donors.
Transient, minor increases in alkaline phosphatase, LDH, SGOT (serum glutamic oxaloacetic transaminase) and uric acid have been reported in normal donors receiving filgrastim; these were without clinical sequelae.
Exacerbation of arthritic symptoms has been observed very rarely.
Symptoms suggestive of severe allergic reactions have been reported very rarely.
Headaches, believed to be caused by filgrastim, have been reported in PBPC donor studies.
Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been reported in healthy donors and patients following administration of G-CSFs (see section 4.4).
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In SCN patients
Undesirable effects related to filgrastim therapy in SCN patients have been reported and for some their frequencies tend to decrease with time.
The most frequent undesirable effects attributable to filgrastim were bone pain, and general musculoskeletal pain.
Other undesirable effects seen include splenic enlargement, which may be progressive in a minority of cases and thrombocytopenia. Headache and diarrhoea have been reported shortly after starting filgrastim therapy, typically in less than 10% of patients. Anaemia and epistaxis have also been reported.
Transient increases with no clinical symptoms were observed in serum uric acid, lactic dehydrogenase and alkaline phosphatase. Transient, moderate decreases in non-fasting blood glucose have also been seen.
Undesirable effects possibly related to filgrastim therapy and typically occurring in < 2% of SCN patients were injection site reaction, headache, hepatomegaly, arthralgia, alopecia, osteoporosis and rash.
During long term use, cutaneous vasculitis has been reported in 2% of SCN patients. There have been very few instances of proteinuria/haematuria.
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