Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Sandoz Limited, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, United Kingdom
Cyclophosphamide may be used alone or in combination with other chemotherapeutic agents, depending on the indication. Cyclophosphamide is indicated in the treatment of:
Cyclophosphamide should only be used by clinicians experienced in the use of cancer chemotherapy. Cyclophosphamide should only be administered where there are facilities for regular monitoring of clinical, biochemical and haematological parameters before, during, and after administration and under the direction of a specialist oncology service.
Dosage must be individualised. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring (in particular, blood cell monitoring).
In combination with other cytostatics of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary.
Use of hematopoiesis stimulating agents (colony-stimulating factors and erythropoiesis stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.
Prior, during and immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, Cyclophosphamide should be administered in the morning. See section 4.4.
It is within the responsibility of the physician to decide on the use of Cyclophosphamide according to the operative treatment guidelines.
The doses below can be regarded as general guidelines:
Hematologic and solid tumours:
For daily treatment:
3–6 mg/kg body weight (= 120–240 mg/m² body surface area), injected intravenously
For intermittent treatment:
10–15 mg/kg body weight (= 400–600 mg/m² body surface area), injected intravenously, with therapy-free intervals of 2 to 5 days.
For high-dose- intermittent treatment:
20–40 mg/kg body weight (= 800–1600 mg/m² body surface area), injected intravenously, with therapy-free intervals of 21 to 28 days.
As preparation for a bone marrow transplantation: 2 days 60 mg/kg or 4 days 50 mg/kg body weight injected intravenously.
If a busulfan-cyclophosphamide (Bu/Cy) regimen is applied, the first dose of cyclophosphamide must be administered at least 24 hours after the last dose of busulfan (see section 4.4 and 4.5).
Autoimmune diseases: Per month 500–1000 mg/m² body surface area.
Severe hepatic impairment may be associated with a decreased activation of cyclophosphamide. This may alter the effectiveness of the cyclophosphamide treatment and should be considered when selecting the dose and interpreting response to the dose selected. (See section 4.4).
The dose must be reduced in patients with severe hepatic impairment. A dose reduction of 25% is recommended in patients with serum bilirubin concentrations of 3.1–5 mg/100 ml (= 0.053–0.086 mmol/l).
In patients with renal impairment, particularly in patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be considered when determining the dosage in such patients. (See section 4.4). A dose reduction of 50% for a glomerular filtration rate below 10 mL/minute is recommended.
Cyclophosphamide and its metabolites are dialyzable, although there may be differences in clearance depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered. See section 4.4.
In elderly patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal, cardiac, or other organ function, and concomitant diseases or other drug therapy in this population.
Cyclophosphamide has been administered to children. The safety profile of cyclophosphamide in paediatric patients is similar to that of the adult population.
A leukocyte and platelet count should be regularly performed during treatment with cyclophosphamide. It is recommended to adjust the dose, if required, if signs of myelosuppression become evident.
Please refer to the table below. Urinary sediment should also be checked regularly for the presence of erythrocytes.
| Leukocyte count/μl | Platelet count /μl | Dosage |
|---|---|---|
| >4000 | >100 000 | 100% of the planned dose |
| 2500–4000 | 50 000–100 000 | 50% of the planned dose |
| <2500 | <50 000 | Omit until values normalise or decide individually |
In combination therapy further dose reductions may have to be considered.
Cyclophosphamide is inert until activated by enzymes in the liver. However, as with all cytotoxic agents, it is recommended that reconstitution should be performed by trained personnel, in a designated area.
Those handling the preparation should wear protective gloves. Care should be taken to avoid splashing material into the eyes. The material should not be handled by women who are pregnant or who are breast-feeding.
The choice of solvent for reconstituting Cyclophosphamide containing cyclophosphamide depends on the route of administration to be used.
If the solution is to be used for IV infusion, Cyclophosphamide (containing cyclophosphamide) is reconstituted by adding sterile water for injection or 0.9% sterile sodium chloride solution.
Reconstituted Cyclophosphamide should be further diluted in 5% dextrose or 0.9% sodium chloride solution prior to infusion.
If the solution is to be used for direct injection, Cyclophosphamide (containing cyclophosphamide) is reconstituted by adding 0.9% sterile sodium chloride solution.
Please note that only Cyclophosphamide reconstituted in 0.9% sterile sodium chloride solution is suitable for bolus injection.
Cyclophosphamide (containing cyclophosphamide) reconstituted in water is hypotonic and should not be injected directly.
For detailed instruction on reconstitution please refer to section 6.6.
Intravenous administration should preferably be conducted as an infusion.
To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g. facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly. Duration of the infusion (ranging from 30 minutes to 2 hours) should be appropriate for the volume and type of carrier fluid to be infused.
Before intravenous use, the substance must be completely dissolved.
Drug products for intravenous use must be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno occlusive hepatic disease, and stomatitis. See section 4.4.
Patients who received an overdose should be closely monitored for the development of toxicities, and hematotoxicity in particular.
There is no specific antidote for an overdosage of cyclophosphamide.
Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid haemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.
Overdosage should be managed with supportive measures, including appropriate, state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity, should it occur.
Cystitis prophylaxis with mesna can help to prevent or reduce urotoxic effects in case of cyclophosphamide overdosage.
Shelf life: 2 years.
Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C for the reconstituted solution.
From a microbiological point of view, the reconstituted solution should be used immediately, unless reconstitution has taken place in controlled and validated aseptic conditions. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C.
Do not store above 25°C.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
Cyclophosphamide, Powder for Solution for Injection or Infusion, is available in the following pack sizes: 1, 5 or 10 clear colourless 100 ml Type I-glass vials containing 1000 mg cyclophosphamide sealed with bromobutyl rubber stopper, and secured with a flip-off seal with a sea green PP button
Not all pack sizes may be marketed.
Vials are packed with or without a protective plastic overwrap (Onco-Safe). “Onco-Safe” does not come into contact with the medicinal product and provides additional transport protection, which increases the safety for the medical and pharmaceutical personnel.
For each 100 mg of cyclophosphamide, 5 ml of solvent must be added for reconstitution.
The choice of diluent for reconstituting Cyclophosphamide containing cyclophosphamide depends on the route of administration to be used.
If the solution is to be used for direct injection, Cyclophosphamide (containing cyclophosphamide) is reconstituted by adding 0.9% sterile sodium chloride solution.
If the solution is to be used for IV infusion, Cyclophosphamide (containing cyclophosphamide) is reconstituted by adding sterile water for injection or 0.9% sterile sodium chloride solution.
The following quantities of water for injections or sodium chloride 0.9% are added to the vials containing Cyclophosphamide, Powder for Solution for Injection or Infusion.
Vial of 500 mg: 25 ml
Vial of 1000 mg: 50 ml
Vial of 2000 mg: 100 ml
Injecting the solvent into the vial for injection creates an abnormally high pressure, which disappears as soon as the second sterile needle has been inserted in the rubber stop of the vial for injection. The powder easily dissolves when the vial for injection is shaken vigorously to produce a clear solution. If the powder does not immediately dissolve, continue to shake the vial vigorously for up to several minutes until complete dissolution of the powder. The solution must be administered as soon as possible following its reconstitution.
After reconstitution the solution is clear and colourless to light yellow. Please check the vial before further use. Only clear solutions must be used.
Cyclophosphamide, Powder for Solution for Injection or Infusion reconstituted in water for injection has an osmolality of 92 mOsm/kg.
Cyclophosphamide, Powder for Solution for Injection or Infusion reconstituted in 0.9% sodium chloride has an osmolality of 353 mOsm/kg and a pH of 4.6
Intravenous administration should preferably be conducted as an infusion.
Reconstituted Cyclophosphamide should be further diluted in 5% dextrose or 0.9% sodium chloride injection prior to infusion.
Please note that only Cyclophosphamide reconstituted in 0.9% sterile sodium chloride solution is suitable for bolus injection.
Cyclophosphamide (containing cyclophosphamide) reconstituted in water is hypotonic and should not be injected directly.
The rules and regulations for handling cytostatics in general must be observed when reconstituting or handling Cyclophosphamide. Reconstitution must, to the extent possible, be performed in a laminar air flow safety cabinet. The person handling the product must wear a protective mask and protective gloves. In case of spills, the area must be thoroughly rinsed with water. If Cyclophosphamide, Powder for Solution for Injection or Infusion is stored (e.g. during transport) at the temperature exceeding the maximum temperature, cyclophosphamide may melt. Vials for injections containing melted cyclophosphamide can be visually recognised. Cyclophosphamide is a white powder. Melted cyclophosphamide is a clear or yellowish viscous liquid (usually found as droplets in the affected vials.). Vials for injections containing melted cyclophosphamide may no longer be used.
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