Cyclophos

Cyclophosphamide.

500 mg: Each vial contains: Cyclophosphamide equivalent to anhydrous Cyclophosphamide 500 mg.
1 g: Each vial contains: Cyclophosphamide (as monohydrate) 1 g.

Pharmacotherapeutic group: Antineoplastic and Immunomodulating Agents; Antineoplastic agents. Alkylating agents. Nitrogen mustard analogues.
Pharmacology: Pharmacodynamics: Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types.
500 mg: Cyclophosphamide engages probably to the S- or G2-phase of the cell cycle.
It remains to be shown whether the cytostatic effect is entirely dependent on the alkylation of DNA or other mechanisms such as inhibition of chromatin transformation processes or inhibition of DNA polymerases play a role. The metabolite acrolein has no antineoplastic activity, but is responsible for the adverse urotoxic effect.
The immunosuppressive effect of Cyclophosphamide is based on the fact that Cyclophosphamide has an inhibitory effect on B-cells, CD4 + T-cells and to a lesser extent on CD8 +-T-cells. In addition, it is assumed that Cyclophosphamide has an inhibitory effect on the suppressor that regulate the IgG2 class of antibodies.
Cross-resistance, especially with structurally related cytotoxic agents, e.g. ifosfamide, as well as other alkylating agents, cannot be excluded.
1 g: The active metabolites of Cyclophosphamide are alkylating agents which transfer alkyl groups to DNA during the process of cell division, thus preventing normal synthesis of DNA.
Mechanism of Action: Cyclophosphamide belongs to the group of alkylating agents which binds to DNA usually via the binding of alkyl groups. As a result, a reactive intermediary is formed which binds to DNA and causes single or double stranded DNA break and may crosslink the chains of DNA thus, disturbing the fundamental mechanisms concerned with cell growth, mitotic activity, differentiation and function. The effects of the alkylating agent although dependent on proliferation, are not cell cycle specific and hence the drug may act on cells at any stage of cycle.
Pharmacokinetics: 500 mg: Cyclophosphamide is administered as an inactive prodrug that is activated in the liver.
Absorption: Cyclophosphamide is quickly and almost completely absorbed from parenteral sites.
Distribution: Less than 20% of Cyclophosphamide is bound to plasma proteins. The protein binding of the metabolites of cyclophosphamide is higher but less than 70%. To what extent the active metabolites protein bound, is not known.
Cyclophosphamide is found in the cerebrospinal fluid and the mother's milk. Cyclophosphamide and metabolites can pass through the placenta.
Metabolism: Cyclophosphamide is activated in the liver to the active metabolites 4-hydroxy-cyclophosphamide and aldofosfamide (tautomeric form of 4-hydroxy-cyclophosphamide) through phase I metabolism by cytochrome P450 (CYP) enzymes. Different CYP isozymes contribute to the bioactivation of Cyclophosphamide, including CYP2A6, 2B6, 2C9, 2C19 and 3A4, 2B6 in which it exhibits highest 4-hydroxylase activity. Detoxification is done mainly through glutathione-S-transferases (GSTA1, GSTP1) and alcohol dehydrogenase (ALDH1, ALDH3). Two to four hours after administration of Cyclophosphamide, the plasma concentrations of the active metabolites are maximal, after which a rapid decrease of plasma concentrations takes place.
Elimination: The plasma half-life of Cyclophosphamide is about 4 to 8 hours in adults and children. The plasma half-lives of the active metabolites are not known.
Following high-dose IV administration within the framework of allogeneic bone marrow transplantation, the plasma concentration of pure Cyclophosphamide follows linear first-order kinetics. Compared with conventional Cyclophosphamide therapy, there is an increase in inactive metabolites, indicating saturation of activating enzyme systems, but not of the stages of metabolism leading to inactive metabolites. During the course of high-dose Cyclophosphamide therapy over several days, there is a decrease in the areas under the plasma concentration-time curve of the parent compound, probably due to auto-induction of microsomal metabolism activity.
Cyclophosphamide and its metabolites are primarily excreted by the kidneys.
1 g: Cyclophosphamide is absorbed from the gastrointestinal tract and from parenteral application sites. It is well absorbed after oral administration with a bioavailability greater than 75%. Peak levels are reached 1-3 hrs. after oral administration. The unchanged drug has an elimination half-life of 3-12 hrs. Several cytotoxic and non-cytotoxic metabolites have been identified in urine and in plasma. Concentration of drug reaches a maximum in plasma 2-3 days after an I.V. dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent of 60%. The distributing volume is about 0.69 L/kg indicating that Cyclophosphamide is distributed in all body fluids including the brain (CSF). Cyclophosphamide is capable of crossing the placental barrier. It is also found in the breastmilk. Total body-clearance of Cyclophosphamide is approximately 82 mL/min and by hepatic metabolism. Only 13% of Cyclophosphamide is excreted unchanged in urine. Metabolites are ultimately eliminated primarily by kidneys, the main urinary metabolite being carboxyphosphamide.

Used in the treatment of various forms of malignancies such as Burkitt's and other non-Hodgkin's lymphomas, multiple myeloma and mycosis fungoides. It is also used in gestational trophoblastic tumours and malignancies of the brain, breast, endometrium, lung, and ovary; in childhood malignancies such as neuroblastoma, retinoblastoma, Wilms' tumour and in sarcomas and some leukemias.
500 mg: It is also indicated for the treatment of immune-mediated conditions such as severe rheumatoid arthritis, systemic lupus erythematosus, vasculitis, dermatomyositis, and intestitular lung disease.

Initial treatment is given by intravenous injection. After satisfactory remission has occurred, maintenance therapy with tablets is recommended. Individual dosage should take into account the general state of the patient and the WBC count.
Daily IV injection of Cyclophosphamide 3-6 mg/kg body weight (120-240 mg/m²) twice weekly.
Massive Intermittent therapy - Cyclophosphamide 10-15 mg/kg body weight (400-600 mg/m²) with therapy free intervals of 7-10 days.
Massive Intermittent therapy - Cyclophosphamide 20-40 mg/kg body weight (800-1600 mg/m²) in divided doses over a period of 2-5 days with therapy free intervals of 10-20 days.
Or as prescribed by the physician.
The IV preparation is dissolved in sterile water for injection to yield a concentration of 20 mg/mL. The vials should be shaken until complete dissolution of the dry substance is obtained. A solution thus prepared is added to 250 mL 5% glucose and administered as a brief infusion of 30 min.

No specific antidote for cyclophosphamide overdosage is known. It should be managed with supportive measures including appropriate treatment for any concurrent infection which may occur.

Cyclophosphamide should not be taken by patients with known hypersensitivity to oxazaphosphorines and in cases of severe bone marrow depression.
Use in Pregnancy: Cyclophosphamide can cause fetal harm when administered to a pregnant woman. Therefore, if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child bearing potential should be advised to avoid pregnancy during Cyclophosphamide therapy.
Use in Lactation: Cyclophosphamide is excreted in breast milk. Therefore, nursing should be discontinued while the patient is on Cyclophosphamide therapy.

Since Cyclophosphamide is a cytotoxic anticancer drug, procedures for proper handling and disposal of such drug should be followed.
Myelosuppression is frequently encountered with Cyclophosphamide; hematologic profile especially neutrophils and platelets should be monitored regularly to determine the degree of hematopoietic suppression.
The urinary sediment should be monitored regularly for red blood cells which may proceed to hemorrhagic cystitis. To prevent toxicity of urinary bladder, large quantities of fluid should be taken during or immediately after administration of Cyclophosphamide.
Prior to initiation of therapy, all conditions of hampered urinary flow in the efferent urinary passages should be excluded and disturbance of electrolyte balance should be corrected.
Patients of both sexes of reproductive age should take contraceptive measures throughout treatment with Cyclophosphamide and for at least six months after its termination so as to preclude any risk of conception.
Patients with impaired renal and hepatic function must be monitored carefully. In cases of patients with severe renal impairment, Cyclophosphamide dosage and reduction may be required.
Patients should be advised to maintain oral and dental hygiene to prevent infections.
Effects on ability to drive and use machines: Patients undergoing treatment with Cyclophosphamide may experience undesirable effects (including nausea, vomiting, dizziness, blurred vision, visual impairment) which could affect the ability to drive or use machines. The decision to drive or operate machinery should be made on an individual basis.

500 mg: Women of childbearing potential: Girls treated with Cyclophosphamide during pre-pubescence generally develop secondary sexual characteristics normally and have regular menses.
Girls treated with Cyclophosphamide during pre-pubescence subsequently have conceived.
Girls treated with Cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause (cessation of menses before age of 40 years).
Contraception in males and females: Women should not become pregnant during the treatment and for a period of 12 months following discontinuation of the therapy.
Men should not father a child during the treatment and for a period of 6 months following discontinuation of the therapy.
Sexually active women and men should use effective methods of contraception during these periods of time.
Pregnancy: There are very limited data from the use of Cyclophosphamide in pregnant women. There are reports of serious multiple congenital aberrations after use during the first trimester.
Animal studies have shown teratogenicity and other reproduction toxicity.
Considering the data from human case reports, animal studies and the mechanism of action of Cyclophosphamide, its use during pregnancy, in particular during the first trimester, is not recommended.
In each individual case the potential benefit of the treatment should be weighed against the potential risk for the foetus.
Breastfeeding: Cyclophosphamide is excreted into the breast milk and can cause neutropenia, thrombocytopenia, low haemoglobin, and diarrhoea in children. Cyclophosphamide is contraindicated during breastfeeding.
Fertility: Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. In women Cyclophosphamide may cause transient or permanent amenorrhea, and in boys treated with Cyclophosphamide during pre-pubescence, oligospermia or azoospermia. Men treated with Cyclophosphamide may develop oligospermia or azoospermia. Prior to treatment of men with Cyclophosphamide, they should be informed of the possibility to store and keep viable sperm collected before treatment.
1 g: Pregnancy: Cyclophosphamide is contraindicated in pregnancy. Cyclophosphamide crosses the placental barrier. Treatment with Cyclophosphamide has a genotoxic effect and may cause fetal damage when administered to pregnant women. Both women and men should wait at least 6 to 12 months after stopping Cyclophosphamide before attempting to conceive or father a child.
Malformations have been reported in children born to mothers treated with Cyclophosphamide during the first trimester of pregnancy. However, there are also reports of children without malformations born to women exposed during the first trimester.
Exposure to Cyclophosphamide in utero may cause miscarriage, fetal growth retardation, and foetotoxic effects manifesting in the newborn, including leukopenia, anaemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.
Animal data suggest that an increased risk of failed pregnancy and malformations may persist after discontinuation of Cyclophosphamide as long as oocytes/follicles exist that were exposed to Cyclophosphamide during any of their maturation phases.
If Cyclophosphamide is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus.
Breastfeeding: Cyclophosphamide is passed into the breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in children breast fed by women treated with Cyclophosphamide. Women must not breastfeed during treatment with Cyclophosphamide.
Fertility: Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.
Development of sterility appears to depend on the dose of Cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment.
Cyclophosphamide-induced sterility may be irreversible in some patients.
Sexually active women and men should use effective methods of contraception during these periods of time.
Female patients: Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotrophin secretion develops in a significant proportion of women treated with Cyclophosphamide.
For older women, in particular, amenorrhea may be permanent.
Oligomenorrhea has also been reported in association with Cyclophosphamide treatment.
Girls treated with Cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and have regular menses.
Girls treated with Cyclophosphamide during prepubescence subsequently have conceived.
Girls treated with Cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause (cessation of menses before age of 40 years).
Male patients: Men treated with Cyclophosphamide may develop oligospermia or azoospermia, which are normally associated with increased gonadotrophin but normal testosterone secretion.
Sexual potency and libido generally are unimpaired in these patients.
Boys treated with Cyclophosphamide during prepubescence may develop secondary sexual characteristics normally, but may have oligospermia or azoospermia.
Some degree of testicular atrophy may occur.
Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

Haematologic: Prolonged use of high doses may induce myelosuppression especially leukopenia. Leukocyte count less than 2000 cells/mm³ develops commonly in patients treated with an initial loading dose of the drug and less frequently in patients maintained on small doses. Thrombocytopenia and anaemia develop occasionally in patients treated with Cyclophosphamide. These effects can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins after 7-10 days of cessation of therapy.
Gastrointestinal: Nausea and vomiting commonly occur with Cyclophosphamide therapy. Anorexia and less frequently, abdominal discomfort or pain and diarrhea may occur. Antiemetic therapy should be initiated to reduce the incidence of nausea and vomiting.
Dermatologic: Alopecia occurs commonly in patients treated with Cyclophosphamide but it is reversible. Pigmentation of the skin and changes in nails can occur.
Urologic: Hemorrhagic cystitis may develop in patients treated with Cyclophosphamide. These adverse effects appear depending on the dose of Cyclophosphamide and the duration of therapy and is thought to be due to Cyclophosphamide metabolites excreted in urine. Ample fluid intake during or immediately after administration of Cyclophosphamide and increased diuresis help to prevent the development of hemorrhagic cystitis. Haematuria usually resolves in a few days after Cyclophosphamide treatment is stopped but may persist in a few cases. In patients receiving doses of 10 mg/kg body weight or more and in high risk patients, concomitant administration of Mesna for protection of urinary bladder, is advisable.
Interference with gonadal function: Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of Cyclophosphamide, duration of therapy and state of gonadal function at the start of the treatment.
Infections: Treatment with Cyclophosphamide may cause significant suppression of immune responses. Serious, sometimes fatal infections may develop in severely immunosuppressed patients. Cyclophosphamide treatment may not be indicated or should be interrupted or the dose reduced in patients who have or who develop viral, bacterial, fungal, protozoal or helminthic infections.
Others: Rare instances of anaphylactic reactions have been reported but are not typical for Cyclophosphamide.

Concomitant use of antidiabetic drugs with Cyclophosphamide may potentiate the reduction in blood sugar level.
If Cyclophosphamide and allopurinol are given concomitantly, there may be an increased in bone marrow depression. Cyclophosphamide treatment causes a marked persistent inhibition of cholinesterase activity and potentiates the effect of succinyl choline chloride.

500 mg: Directions for Reconstitution: The IV preparation is dissolved in 25 mL of sterile water for injection to yield a concentration of 20 mg/mL. The vials should be shaken until complete dissolution of the dry substance is obtained. A solution thus prepared is added to 250 mL 5% glucose and administered as a brief infusion of 30 min. Single dose. Discard any remaining portion.
1 g: Directions for Reconstitution/Dilution: Dissolve the contents in 50 mL of sterile water for injection. Shake until dissolved.
The IV preparation is dissolved in sterile water for injection to yield a concentration of 20 mg/mL. The vial should be shaken until complete dissolution of the dry substance is obtained. Thus, the prepared solution is added to 250 mL of 5% glucose and is administered as a brief infusion for 30 min.
Special Precautions for Disposal and Other Handling: For intravenous administration: Cyclophosphamide Injection is compatible with the following infusion solutions: sodium chloride solution, glucose solution, sodium chloride and glucose solution, sodium chloride and potassium chloride solution, and potassium chloride and glucose solution.
For oral administration: Cyclophosphamide reconstituted Injection may be dissolved in Aromatic Elixir USP.
General instructions: If vials are stored above the recommended temperature this can cause degradation of the active ingredient, identifiable by a yellow melted appearance to the vial contents. Vials containing melted material should not be used.
Cyclophosphamide is a cytotoxic agent. The handling and preparation of Cyclophosphamide should always be in accordance with current guidelines on safe handling of cytotoxic agents. The material should not be handled by women who are pregnant or who are breast-feeding.
Adequate care and precautions should be taken in the disposal of empty vials and items (syringes, needles, etc) used in reconstitution and administration.

Store at temperatures not exceeding 25°C. Protect from light.

Cytotoxic Chemotherapy

L01AA01 - cyclophosphamide ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.

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