Cyclophosphamide 50 Tablets

1. Name Of The Medicinal Product

Cyclophosphamide Tablets.

2. Qualitative And Quantitative Composition

Cyclophosphamide monohydrate BP 53.50 mg equivalent to 50 mg anhydrous cyclophosphamide.

3. Pharmaceutical Form

Sugar-coated tablets

4. Clinical Particulars

4.1 Therapeutic Indications

Alkylating, antineoplastic agent. Cyclophosphamide has been used successfully to induce and maintain regressions in a wide range of neoplastic conditions, including leukaemias, lymphomas, soft tissue and osteogenic sarcomas, paediatric malignancies and adult solid tumours; in particular, breast and lung carcinomas.

Cyclophosphamide is frequently used in combination chemotherapy regimens involving other cytotoxic drugs.

4.2 Posology And Method Of Administration

Route of administration: Oral.

Adults and children: The recommended dose for cyclophosphamide tablets is 50-250 mg/m² daily (doses towards the upper end of this range should be used only for short courses).

The dose may be amended at the discretion of the physician.

It is recommended that the calculated dose of cyclophosphamide be reduced when it is given in combination with other antineoplastic agents or radiotherapy, and in patients with bone marrow depression.

Cyclophosphamide tablets should be swallowed whole, preferably on an empty stomach, but if gastric irritation is severe, they may be taken with meals.

A minimum output of 100 ml/hour should be maintained during therapy with conventional doses to avoid cystitis. If the larger doses are used, an output of at least this level should be maintained for 24 hours following administration, if necessary by forced diuresis. Alkalinisation of the urine is not recommended.

Cyclophosphamide should be given early in the day and the bladder voided frequently. The patient should be well hydrated and maintained in fluid balance.

Mesna (Uromitexan) can be used concurrently with cyclophosphamide to reduce urotoxic effects (for dosage see Uromitexan data sheet). If Mesna (Uromitexan) is used to reduce uroethelial toxicity, frequent emptying of the bladder should be avoided.

If the leucocyte count is below 4,000/mm³ or the platelet count is below 100,000/mm³, treatment with cyclophosphamide should be temporarily withheld until the blood count returns to normal levels.

4.3 Contraindications

Hypersensitivity and haemorrhagic cystitis.

4.4 Special Warnings And Precautions For Use

Cyclophosphamide should be withheld in the presence of severe bone marrow depression and reduced doses should be used in the presence of lesser degrees of bone marrow depression. Regular blood counts should be performed in patients receiving cyclophosphamide.

It should not normally be given to patients with severe infections and should be withdrawn if such infections become life threatening.

Cyclophosphamide should be used with caution in debilitated patients and those with renal and/or hepatic failure. Cyclophosphamide is not recommended in patients with a plasma creatinine greater than 120 µmol/l (1.5 mg/100 ml) bilirubin greater than 17 µmol/l (1 mg/100 ml); or serum transaminases or alkaline phosphatase more than 2-3 times the upper limit of normal. In all such cases, dosage should be reduced.

Cyclophosphamide should be used only under the directions of physicians experienced in cytotoxic or immunosuppressant therapy.

Further Information: The dosage regimen for mesna (Uromitexan) varies according to the dose of cyclophosphamide administered. In general i.v. Uromitexan is given as 60% w/w of the dose of i.v. Cyclophosphamide in three equal doses of 20% at 0, 4 and 8 hours. With the higher doses of cyclophosphamide, the dose and frequency of administration may need to be increased. Uromitexan Tablets are also available; full prescribing information for both presentation is available on the appropriate data sheet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Oral hypoglycaemic agents may be potentiated by cyclophosphamide.

4.6 Pregnancy And Lactation

This product should not normally be administered to patients who are pregnant or to mothers who are breast feeding. Alkylating agents, including cyclophosphamide, have been shown to possess mutagenic, teratogenic and carcinogenic potential. Pregnancy should therefore be avoided during cyclophosphamide therapy and for three months thereafter.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Single doses will produce a leucopenia which may be severe but usually returns to normal within 21 days.

Depression of the reticuloendothelial system with granulopoiesis and lymphopoiesis being more affected than thrombopoiesis and erythropoiesis. This depression, however, is reversible.

Amenorrhoea and azoospermia often occur during treatment with cyclophosphamide but in most cases are reversible.

Haematuria may occur during or after therapy with Cyclophosphamide. Cyclophosphamide is excreted mainly in the urine, largely in the form of active metabolites which may give rise to a chemical cystitis which may be haemorrhagic. Acute sterile haemorrhagic cystitis may occur in up to 10% of patients not given mesna (Uromitexan) in conjunction with Cyclophosphamide. Late sequelae of this cystitis are bladder contracture and fibrosis.

Because of this, a high fluid intake should be maintained with frequent emptying of the bladder. Cyclophosphamide therapy may lead to inappropriate secretion of anti-diuretic hormone, fluid retention and hyponatremia, with subsequent water intoxication. Should this arise, a diuretic may be given. Cyclophosphamide may cause myocardial toxicity, especially at high dosage.

Cyclophosphamide may induce permanent sterility in children.

In addition to those noted above, the following may accompany cyclophosphamide therapy: hair loss, which may be total, although generally reversible; mucosal ulcertation; anorexia, nausea and vomiting; pigmentation, typically affecting the palms and nails of the hands and the soles of the feet, and interstitial pulmonary fibrosis.

Hepatic toxicity has rarely been reported.

Cyclophosphamide has been shown to be mutagenic, teratogenic, and carcinogenic in certain laboratory tests and as with other cytotoxic agents, there have been reports of possible drug-induced neoplasia. There is an excessive risk of acute leukaemia and bladder cancer following cyclophosphamide therapy.

An alteration in carbohydrate metabolism may be seen in patients on cyclophosphamide. Other side effects, such as pancreatitis, macrocytosis, and induction of hyperglycaemia or hypoglycaemia have been reported.

There are certain complications such as veno-occlusive disease, thromboembolism, disseminated intravascular coagulation or haemolytic uraemic syndrome, that may also be induced by the underlying disease, but which might occur with an increased frequency during chemotherapy that includes cyclophosphamide.

Side effects have occasionally occurred after cessation of therapy.

4.9 Overdose

Myelosuppression (particularly granulocytopenia) and haemorrhagic cystitis are the most serious consequences of overdosage. Recovery from myelosuppression will occur by the 21st day after the overdosage in the great majority of patients (at doses up to 200 mg/kg i.v.) while granulocytopenia is usually seen by day 6 and lasts for a mean period of 12 days (up to 18 days). A broad spectrum antibiotic may be administered until recovery occurs. Transfusion of whole-blood, platelets or white cells and reverse barrier nursing may be necessary.

If the drug has been taken in the form of tablets, early gastric lavage may reduce the amount of drug absorbed.

During the first 24 hours and possibly up to 48 hours after overdosage, i.v. mensa may be beneficial in ameliorating damage to the urinary system. Normal supportive measures such as analgesics and maintenance of fluid balance should be instituted. If the cystitis does not resolve more intensive treatment may be necessary.

No further courses should be given until the patient has fully recovered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cyclophosphamide is an antineoplastic agent which is converted in the body to an active alkylating metabolite. It also possesses marked immunosuppressant properties. The principal site of cyclophosphamide activation is the liver. The chemotherapeutic and immunosuppressant activity of cyclophosphamide is thought to be mediated by the cytotoxic intermediates produced by activation by mixed function oxidases in hepatic microsomes. Non-enzymatic cleavage, possibly taking place in the tumour cells, results in the formulation of highly cytotoxic forms of the drug.

5.2 Pharmacokinetic Properties

Cyclophosphamide may be incompletely absorbed from the gastro-intestinal tract. It rapidly disappears from the plasma and peak concentrations occur about 1 hour after an oral dose.

The metabolites of cyclophosphamide are excreted in the urine and these have an irritant effect on the bladder mucosa. Unchanged drug is also excreted in the urine and accounts for only 5-25% of the administered dose.

Metabolites have been found to be more protein bound than the parent compound.

5.3 Preclinical Safety Data

No further preclinical data are available.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Pregelatinised starch

Lactose monohydrate

Gelatin

Microcrystalline cellulose

Sodium stearyl fumarate

Magnesium stearate

Coating

Polyethylene glycol

Sucrose

Maize starch

Calcium carbonate

Povidone

Opalux AS-9486 consisting of

- titanium dioxide

- red iron oxide

- yellow iron oxide

- sucrose

- purified water

- polyvinylpyrrolidone

- sodium benzoate

Carnauba wax

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original container in order to protect from moisture.

6.5 Nature And Contents Of Container

White polyethylene containers with polyethylene snap-caps, containing a white capsule of desiccant.

6.6 Special Precautions For Disposal And Other Handling

None stated.

Administrative Data

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

UK

8. Marketing Authorisation Number(S)

PL 00032/0335

9. Date Of First Authorisation/Renewal Of The Authorisation

16 August 2002

10. Date Of Revision Of The Text

January 2010

Ref: CP5_0