ANTINEOPLASTIC AGENT

Baxter Corporation DATE OF PREPARATION: 4 Robert Speck Parkway February 4, 2002 Suite 700 Mississauga, ON L4Z 3Y4 DATE OF REVISION: October 14, 2003

Control No.: 080233

PRODUCT MONOGRAPH

Pr

PROCYTOX(r)

(Cyclophosphamide) Cyclophosphamide Tablets USP: 25 mg, 50 mg 200 mg, 500 mg, 1000 mg, 2000 mg Powder for Injection, Baxter Std.

ANTINEOPLASTIC AGENT

PROCYTOX (CYCLOPHOSPHAMIDE) IS A POTENT DRUG THAT SHOULD ONLY BE USED BY PHYSICIANS EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS OR IMMUNOSUPPRESSIVE THERAPY

EXTREME CAUTION IS RECOMMENDED IN THE USE OF PROCYTOX FOR NON- NEOPLASTIC CONDITIONS, BECAUSE OF POTENTIAL CARCINOGENICITY WITH LONG-TERM USE OF THIS AGENT

ACTIONS AND CLINICAL PHARMACOLOGY

Cyclophosphamide, a nitrogen mustard derivative, is a polyfunctional alkylating agent. The parent drug is inactive in vitro, when tested on cultures of human leukocytes or carcinomatous cells of human origin. The active metabolite of cyclophosphamide, phosphoramide mustard, exhibits the alkylating action. Phosphoramide mustard is formed, following the biological transformation through oxidation by hepatic microsomal enzymes under spontaneous ss-elimination of acrolein from aldophosphamide. The cytotoxic action of the active metabolite is primarily due to crosslinking of DNA and RNA strands, as well as inhibition of DNA synthesis. Cyclophosphamide is a potent immunosuppressive agent that also causes marked and persistent inhibition of cholinesterase activity. Alkylating metabolites of cyclophosphamide have been measured in cerebrospinal fluid, but, only a small fraction crosses the brain barrier.

Pharmacokinetics

Absorption: Cyclophosphamide is well absorbed from the gastrointestinal tract and from parenteral sites. Topical cyclophosphamide, applied to external (body surface) neoplastic tissues, appears to be absorbed. The following demonstrates that cyclophosphamide can be absorbed through intact human skin; therefore, requiring the protective use of unpowdered latex gloves (See PHARMACEUTICAL INFORMATION, Special Instructions).

*CP=cyclophosphamide

Bioavailability:

The systemic availability, estimated from the ratio of areas under serum- concentration-time curves following oral and intravenous cyclophosphamide (CP), was reported as 97% for a 100 mg, and 74% for a 300 mg dose.

Oral CP is approximately 75% absorbed from the gastrointestinal tract. Oral administration demonstrated 3.5 times more alkylating activity than following an intravenous dose. In all the pharmacokinetic measurements in man, large inter-individual variations must be considered.

Distribution:

A mean apparent volume of distribution of cyclophosphamide was 0.56 L/Kg in adults and 0.67 L/Kg in children.

Tissue Distribution

of CP after i.v. administration to cancer patients indicated that both unchanged parent drug and metabolites in small quantities penetrate the blood brain barrier; brain tissue concentrations being similar to those in blood. Biopsies, performed 2 hours after CP infusion, indicated approximately 30% more radioactivity in lymph nodes compared to muscle, adipose tissue or skin, but relative proportions of unchanged drug metabolites were not established.

Protein Binding:

12 to 14% of unchanged cyclophosphamide is protein-bound; the alkylating metabolites, however, are more extensively bound, namely 67% of the total plasma alkylating activity, and in another study, 39% of phosphamide mustard was protein-bound.

Metabolism: While chemically not reactive, the primary metabolites 4-hydroxycyclophosphamide and aldophosphamide are cytotoxic in vitro, and may represent transport forms of the alkylating moiety, phosphoramide mustard. The two primary metabolites can be further oxidized into the major urinary metabolites 5-ketocyclophosphamide and carboxyphosphamide. Nor-nitrogen mustard, a decomposition product of carboxyphosphamide, is an active alkylating agent with cytotoxicity in vivo and in vitro, however, little antitumour activity could be demonstrated; yet, it may play a role in the hematopoietic and other toxicities of cyclophosphamide. Another metabolite formed from aldophosphamide is acrolein, which has been identified as the most urotoxic species.

Disposition Kinetics:

The decline in CP plasma levels following an i.v. dose is biexponential with terminal half-life averaging 7 hours (1.8 to 12.4) for adults, and 4 hours (2.4 to 6.5) for children; daily administration of approximately 50 mg/Kg bid or qid (i.v. infusion) to children significantly decreased both plasma half life and urinary excretion of CP. With daily exposure or repeated high-dose

administration (i.v.) of cyclophosphamide to adult patients, the half-life of CP decreased without an increase in urinary excretion, suggesting that the drug induces its own metabolism. After an i.v. dose, the NBP [4-(nitrobenzyl)-pyridine] plasma alkylating activity peaks 2 hours after administration, and declines with a half-life of 7.7 hours. Phosphoramide mustard in 3 patients, receiving 60-75 mg/Kg cyclophosphamide, peaked 2 to 3 hours after the administration of CP at levels 10 to 20% of the unchanged drug, and declined slowly with levels still detectable at 24 hours. Even with doses as high as 80 mg/Kg, the plasma half-life of CP does not increase. The t1/2 and AUC of cyclophosphamide after a 5-day continuous infusion schedule of 300-400

1/2

mg/m2/day, were similar to the t and AUC of a 1500 mg/m2 i.v. bolus. The AUC of the alkylating activity after 5-day i.v. infusion, however, was three times higher than the AUC of alkylating activity after 1500 mg/m2 i.v. bolus administration of cyclophosphamide. After CP administration to man and laboratory animals, significant differences in the pharmacokinetic parameters of the active metabolite 4-hydroxycyclophosphamide in both man and animals were found. In man, the active metabolite in blood was found at only low but longer lasting concentrations compared to the high and relatively short time concentration in blood of mice and rats, after a comparable dose. Elimination: In man, a generally higher proportion of the administered CP is excreted as metabolites in urine. Urinary recovery of radioactivity after intravenously administered 14C-cyclophosphamide to patients ranged from 59 to 82% after 4 days, while not more than 20% of i.v. cyclophosphamide was excreted unchanged in urine at any dose level. Renal clearance estimates of between 5.3 and 11 mL/min indicate substantial renal tubular reabsorption.

Pharmacokinetics in Renal Function Impairment:

Patients with severe renal function impairment have a normal biotransformation of cyclophosphamide, but impaired excretion of metabolites with significantly higher plasma alkylating activity. Dose modification of cyclophosphamide, related to the degree of renal dysfunction, may be advised. Patients with moderate to severe renal impairment receiving high doses of cyclophosphamide or those with severe renal impairment receiving conventional doses may require dose reduction, e.g., a dose reduction of 50% for a glomerular filtration rate below 10 mL/minute is recommended.

Cyclophosphamide is dialysable with a high extraction efficiency.

Pharmacokinetics in Hepatic Function Impairment:

A patient with Hodgkin's disease showing jaundice, markedly elevated alkaline phosphatase and filling defects on liver scan had the longest cyclophosphamide half life (8.4 hrs) and lowest peak plasma alkylating metabolite level (4.2

umoles/mL) of 12 patients having received 40 mg/Kg CP. Prior hepatic dysfunction and/or hepatotoxic medication might predispose the patient to oral cyclophosphamide toxicity by altering the balance between the enzymatic production of non-toxic metabolites (carboxyphosphamide) and the decomposition of aldophosphamide to the effective alkylating agent phosphoramide mustard.

CONTRAINDICATIONS

Cyclophosphamide is contraindicated in patients with severely depressed bone marrow function; particularly after previous or during concurrent chemo- and/or radiation therapy without appropriate reduction in dosage.

CAUTION

is indicated, when administering cyclophosphamide to patients with severe leukopenia, thrombocytopenia, and tumor cell infiltration of bone marrow.

Cyclophosphamide is contraindicated in patients who have demonstrated hypersensitivity to this drug or its metabolites, alone or as part of combination chemotherapy. Because of the mutagenic and teratogenic potential of PROCYTOX (cyclophosphamide) adequate methods of contraception should be used by patients (both female and male) during treatment with PROCYTOX. The duration of contraception in men and women after the end of chemotherapy depends on the prognosis of the primary disease and on the intensity of the parents' desire for a child. Men should be informed about sperm preservation prior to initiation of treatment with PROCYTOX. Cyclophosphamide-induced malignancy, mutagenicity, or impairment of fertility must be considered in any risk/benefit assessment. Use during pregnancy; primarily during the first trimester. If pregnancy occurs during cyclophosphamide treatment, the patient must be informed about the possible risks to the fetus. Use during breast feeding. Since cyclophosphamide is distributed into breast milk, breast- feeding is not recommended during chemotherapy, due to the potential risks to the infant (adverse effects, carcinogenicity, mutagenicity). Since varicella-zoster infections appear to be particularly dangerous, concomitant use of cyclophosphamide must be avoided. With all acute infections, caution is indicated when administering cyclophosphamide. Use in patients with inflammation of the bladder (cystitis). Use in patients with urinary outflow obstructions. In combined chemotherapy regimen, the contraindications for each individual drug must be identified.

WARNINGS

EXTREME CAUTION IS RECOMMENDED IN THE USE OF PROCYTOX (CYCLOPHOSPHAMIDE) FOR NON-NEOPLASTIC CONDITIONS, BECAUSE OF POTENTIAL CARCINOGENICITY WITH LONG-TERM USE OF THIS AGENT.

SINCE CYCLOPHOSPHAMIDE IS AN INHIBITOR OF SERUM CHOLINESTERASE, PATIENTS RECEIVING THIS DRUG MAY EXHIBIT INCREASED SENSITIVITY TO NEUROMUSCULAR BLOCKING AGENTS, SUCH AS SUCCINYLCHOLINE. IF A PATIENT WHO IS TO UNDERGO SURGERY IS RECEIVING CYCLOPHOSPHAMIDE OR HAS BEEN TREATED WITH CYCLOPHOSPHAMIDE WITHIN 10 DAYS OF GENERAL ANESTHESIA, THE ANESTHETIST SHOULD BE SO ADVISED PRIOR TO SURGERY.

THE RATE OF METABOLISM AND THE LEUCOPENIC ACTIVITY OF PROCYTOX ARE INCREASED BY CHRONIC ADMINISTRATION OF PHENOBARBITAL.

PROCYTOX HAS BEEN SHOWN TO BE MORE TOXIC IN ADRENALECTOMIZED DOGS. DOSE ADJUSTMENTS OF PROCYTOX MAY BE NECESSARY FOR ADRENALECTOMIZED PATIENTS

Treatment with PROCYTOX may cause significant suppression of immune responses. Dose modification should be considered for patients who develop bacterial, fungal or viral infections. Prior to initiating treatment with PROCYTOX, it is necessary to exclude or correct any obstructions of the efferent urinary tract, cystitis, infections and electrolyte imbalances. Bladder injury such as hemorrhagic cystitis, or fibrosis of the bladder may develop in patients on long-term cyclophosphamide therapy. Should a cystitis in connection with micro- or macrohematuria appear during treatment with PROCYTOX, therapy must be interrupted until normalization.

PRECAUTIONS

PROCYTOX (CYCLOPHOSPHAMIDE) IS A POTENT DRUG THAT SHOULD ONLY BE USED BY PHYSICIANS EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS OR IMMUNOSUPPRESSIVE THERAPY.

* *The patient's hematologic, hepatic and urinary profile must regularly be monitored. * *

Leukocyte counts must be conducted regularly during treatment: at intervals of 5-7 days when starting treatment and every 2 days if the counts drop below 3000/mm3. Daily counts may be necessary under certain circumstances. In patients receiving long-term treatment, counts every two weeks are usually sufficient. If signs of myelosuppression become evident, it is recommended to check the red blood count and the platelet count. Urinary sediment should also be checked regularly for the presence of erythrocytes.

General

Each individual component of a cyclophosphamide-containing poly-chemotherapy regimen must have its precaution profile reviewed. Since cyclophosphamide is highly toxic with a relatively low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity, the drug must only be used under constant supervision of the attending physician. Due to potential adverse effects of cyclophosphamide such as nausea and vomiting which may result in vasomotor ataxia, caution should be advised when driving or operating machinery.

Use in the Elderly

While age-related renal and/or hepatic impairment may require cautious dose adjustment, no geriatrics-specific problems are expected to limit the usefulness of PROCYTOX in the elderly.

Use in Children

No pediatrics-specific problems are documented that would limit the usefulness of PROCYTOX in children. With or without renal and/or hepatic impairment, dosage adjustment in this patient group is necessary.

Patients with Special Diseases and Conditions

Previous therapy with other cytotoxic agents Previous X-ray therapy Hyperuricemia (Gout and/or urate renal stones or history thereof)

Drug Interactions

Cyclophosphamide (<10 mg/Kg i.v.) and indomethacin (50 mg p.o. qid). Four (4) cases of severe pulmonary edema and acute life-threatening water intoxication. Appropriate supportive measures should be employed if water intoxication occurs Cyclophosphamide (100-150 mg p.o.) and prednisone (20-80 mg p.o. ). Four (4) cases of acute respiratory failure; three patients died. Cyclophosphamide (10 mg/Kg infusion) and succinylcholine anesthesia. Post-operative apnea, which is not reduced with smaller doses of cyclophosphamide. Prior or concurrent treatment with hepatic enzyme inducers such as phenobarbital, phenytoin, benzodiazepines and/or chloral hydrate may induce microsomal metabolism to increase formation of alkylating metabolites of cyclophosphamide, thereby reducing the half-life and increasing the activity of cyclophosphamide. Cyclophosphamide (15-20 mg/Kg 14C) and phenobarbitone (60 mg p.o. tid). Cyclophosphamide half- life decreased from 4.3 hours to 1.6 hours; however, in another study, cyclophosphamide biotransformation was increased 2 to 3 fold after phenobarbitone. In these studies, urinary excretion of metabolites over 48 hours was unchanged. Alcohol consumption is not recommended in patients treated with cyclophosphamide. Concurrent cyclophosphamide with allopurinol or hydrochlorothiazide may enhance the bone marrow toxicity of cyclophosphamide. If concurrent use is unavoidable, frequent monitoring for toxic effects is strongly recommended. Concurrent cyclophosphamide with anthracyclines , (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin) may result in increased cardiotoxicity. It is recommended that the total dose of doxo- or daunorubicin does not exceed 400 mg/m2 of body surface. Specific dosing instructions for idarubicin and epirubicin are not available, and their concurrent use with cyclophosphamide should be undertaken with caution after consulting the relevant product information for each product. Pentostatin or radiation towards the cardiac region may result in increased cardiotoxicity in the presence of cyclophosphamide. Concurrent administration of methotrexate and cyclophosphamide may result in the inhibition of the metabolism of cyclophosphamide. (EDI St.Louis, MO 1997, loose leaf, p.9/6.01/1988) The blood glucose-lowering effect of sulfonyl ureas may be intensified when administered concomitantly with cyclophosphamide. Since cyclophosphamide has immunosuppressive effects, the patient can be expected to exhibit a diminished response to any vaccination; injection with activated vaccines may be accompanied by vaccine-induced infection. Concomitant administration of chloramphenicol leads to a prolonged half-life of cyclophosphamide and to a delayed metabolism. Concomitant administration of grapefruit or grapefruit juice is not recommended since grapefruit contains a compound that may impair the activation of cyclophosphamide, and thereby its efficacy. It is prudent to monitor, among others, the following drugs if administered concurrent with cyclophosphamide: Colchicine, Probenecid, Sulfinpyrazone, Cytarabine, Azathioprine, Chlorambucil, Corticosteroids, Glucocorticoid, Cyclosporine, Mercaptopurine, ACE-inhibitors (Pancytopenia is a known ADR of this latter combination), Indomethacin, (see also above EDI-Evaluation of drug interactions- reference). Concurrent use in cardiac transplant patients of cyclophosphamide with the antihyperlipidemic HMG- CoA reductase inhibitor lovastatin may be associated with an increased risk of rhabdomyolysis and acute renal failure.

Laboratory Tests

During treatment, the patient's hematologic profile (particularly neutrophils and platelets) should be monitored regularly, to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells, a possible indicator for hemorrhagic cystitis. Frequent liver function tests (LFT's) are advised. The following laboratory alterations have been reported in the literature and are potentially clinically significant:

Positive reactions may be suppressed:

Candida skin test Mumps skin test Trichophyton skin test Tuberculin PPD skin test

False-positive results may be produced:

Papanicolaou (PAP) test

Serum concentrations may be decreased:

Pseudocholinesterase

Blood and urine concentrations may be increased:

Uric acid

Information to Be Provided to the Patient

< Patients should be fully informed as to treatment options, risks, and safety of PROCYTOX, both alone, or as component of a polychemotherapy regimen. (See DOSAGE AND ADMINISTRATION) < Present information listed in this monograph under CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS.

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Patients must strictly respect dosage instructions and treatment schedules, to ensure efficacy and tolerability of PROCYTOX.

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Prevention of drug interactions and reporting of moderate to severe side effects must carefully be advised.

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Importance of ample fluid intake - some patients may require up to 3000 mL (3 quarts) - and subsequent increase in urine output, as well as frequent voiding to prevent accumulation in the bladder of the toxic metabolite acrolein, suspected of causing hemorrhagic cystitis, and to aid in excretion of uric acid.

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Importance of continuing medication despite stomach upset; patients should be advised about the administration of antiemetics.

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To avoid bruising or injury (accidental cuts). Caution in the use of instruments of dental hygiene, or when dental work is done. Physician may suggest alternatives.

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Wearing a facial mask (nose and mouth), to prevent exposure to persons with bacterial infections, as well as avoiding persons (including family members) who were immunized with oral polio-virus vaccine.

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Not to touch the eyes or inside of nose, unless hands were washed immediately before.

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To notify the attending physician or nurse of any upcoming surgery including dental surgery, to prevent cyclophosphamide (use within 10 days of general anesthesia) interactions with general anesthetic medications.

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To notify the attending physician or nurse of any upcoming immunizations.

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Patients should be informed about the importance of meticulous oral hygiene.

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The recommended storage temperature for the PROCYTOX dosage forms should not exceed 25degC.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Limited information on acute overdosage of cyclophosphamide is available.

Since no specific antidote for cyclophosphamide is known, great caution is advised each time it is used. If overdose of cyclophosphamide is known or suspected, the patient should be hospitalized for general supportive therapy. Cyclophosphamide can be dialysed. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication. A dialysis clearance of 78 mL/min was calculated from the concentration of non-metabolized cyclophosphamide in the dialysate (normal renal clearance is around 5 - 11 mL/min). A second working group reported a value of 194 mL/min. After 6 hours of dialysis, 72% of the dose of cyclophosphamide administered was found in the dialysate. In the case of overdose, myelosuppression, mostly leukocytopenia, is to be expected, among other reactions. The severity and duration of the myelosuppression depends on the extent of the overdose. Frequent checks of the blood count and monitoring of the patient are necessary. If neutropenia develops, infection prophylaxis must be given and infections must be treated adequately with antibiotics. If thrombocytopenia develops, thrombocyte replacement should be ensured according to need. It is essential that cystitis prophylaxis with mesna be undertaken to avoid any urotoxic effects. Cardiotoxicity may also occur with overdosage. In patients who received 4 to 10-day courses of cyclophosphamide with total dosage per course exceeding 140 mg/Kg or 5.2 g/m2, cardiac damage manifested by heart failure occurred within 15 days of the initial dose. Impairment of water excretion with hyponatremia, weight gain, and inappropriately concentrated urine has been reported after cyclophosphamide doses exceeding 50 mg/Kg (2 g/m2). At least one fatal case of cyclophosphamide overdosage had been reported; potentially fatal cardiotoxicity was the most serious consequence of overdosage. The risk of overdose with high-dose cyclophosphamide concomitantly with radiation therapy or other potentially cardiotoxic drugs (e.g: anthracyclines) must carefully be taken into consideration. If a cyclophosphamide solution is inadvertently administered by paravenous injection, there is usually no danger of cytostatic tissue damage since such damage is not expected before cyclophosphamide has been bioactivated in the liver. Nevertheless, if paravasation should occur, stop the infusion immediately and aspirate the paravasate with the cannula in place, irrigate the area with saline solution and immobilize the extremity.

DOSAGE AND ADMINISTRATION

PROCYTOX (CYCLOPHOSPHAMIDE) IS A DRUG WITH THE POTENTIAL FOR FATAL COMPLICATIONS, AND SHOULD, THEREFORE, BE ONLY USED BY A PHYSICIAN EXPERIENCED WITH CANCER CHEMOTHERAPEUTIC DRUGS AND/OR IMMUNOSUPPRESSIVE THERAPY.

Parenteral products prior to administration need to be visually inspected for discolouration and particulate matter. After reconstitution, this parenteral dosage form represents a colourless and clear solution.

During or immediately after the administration of PROCYTOX, adequate amounts of fluid should be ingested and the patient should empty his/her bladder at regular intervals. Prophylactic treatment with mesna is recommended for protection of the bladder (see WARNINGS, PRECAUTIONS, Information to be Provided to the Patient, and ADVERSE REACTIONS).

INITIAL LOADING DOSE:

PROCYTOX

Patients with normal hematologic and bone marrow function:

Patients with compromised bone marrow function due to prior radiation therapy, poly- chemotherapy, or tumour cell infiltration, must have their initial loading dose reduced by 30-50%. Dosage adjustment must also be considered for children and adults with concurrent disease or special conditions.

Morning administration of PROCYTOX is recommended.

The leukocyte count generally serves as a guide to dosage adjustments, and maintaining a range of 2500-4000 cells/mm3 is recommended to possibly avoid infection.

The above initial loading doses may lead to transient or more persistent reduction to 200 cells/mm3.

The patient's hematologic profile must carefully be monitored.

MAINTENANCE DOSE:

PROCYTOX

It is generally advisable to administer the largest maintenance dose that can reasonably be tolerated by the patient, unless the disease is unusually sensitive to cyclophosphamide.

Concurrent disease, special conditions including performance index must lead to dosage adjustment.

POLYCHEMOTHERAPY REGIMEN

As with monotherapy, it is advisable that treatment-related emergency measures and equipment, including pathology-specific antibiotics be physically present during polychemotherapy.

It should be noted that regular and high-dose cyclophosphamide as monotherapy or as component of polychemotherapy are being effectively used in patients resistant to first line treatment such as melphalan or busulfan. Objective responses in a variety of different forms of cancer, plus its relative platelet-sparing effect make cyclophosphamide an alternate drug of choice. Cyclophosphamide as 60 mg/Kg i.v. for 2 days may be administered for bone marrow transplant conditioning. In patients with multiple transfusions, cyclophosphamide is not adequately IMMUNOSUPPRESSIVE, requiring the addition of AT to the retransplant cytoreduction conditioning.

NOTE: Due to constant new developments in cancer chemotherapy, the following presentation can only be viewed as an example of effective treatments. Treatment centre-specific dose and schedule variations, addition of surgery, irradiation and other treatment modalities were not included; descriptions of treatment regimens involving chemotherapy with cyclophosphamide alone or as component of polychemotherapy is the focus of this presentation.

When deciding upon a particular treatment regimen, the literature cited in this section must carefully be reviewed.

HODGKIN'S DISEASE:

Patients with relapsed Hodgkin's disease and presenting marrow abnormality

10,43

C Cyclophosphamide 1.5 g/m2 i.v. daily for 4 consecutive days Carmustine (BCNU) 300 mg/m2 i.v. for 1 day V Etoposide (VP-16) 100-125 mg/m2 i.v. b.i.d. for 3 consecutive days

PSCT CBV

Autologous peripheral stem cell transplantation i.v. following

administration: All blood products were irradiated prior to use. Mesna or continuous bladder irrigation was used to prevent hemorrhagic cystitis.

Patients with relapsed Hodgkin's disease78 Cyclophosphamide 1.5 g/m2 i.v. daily (days -6 to -3) Carmustine(BCNU) 300 mg/m2 i.v. for 1 day (day -6) V Etoposide (VP-16) 125 mg/m2 i.v. b.i.d. (days -6 to -4)

ABMT

Autologous bone marrow transplantation i.v. on day 0, 3 days after end of chemotherapy

rhG-CSF

60 ug/Kg/day (Continuous increase or decrease of AGC = Absolute granulocyte count requires dose adjustment of rhG-CSF) for a maximum of 28 days, beginning on day 1

Note:

For this treatment regimen, all patients received 1 day prior to commencement of chemotherapy 1.0 g oral phenytoin sodium, followed by 300 mg daily for 4 days as prophylaxis against seizures.

Patients with resistant relapsed Hodgkin's disease47 Cyclophosphamide 1.5 g/m2 i.v. daily (days 1-4) Carmustine (BCNU) 300 mg/m2 i.v. on day 1 V Etoposide (VP-16) 150 mg/m2 i.v. daily (days 1-3)

ABMT

Autologous bone marrow transplantation on day 7

Patients with resistant relapsed Hodgkin's disease47 Cyclophosphamide 3.0 g/m2 i.v. days 1 and 2 B Carmustine (BCNU) 200 mg/m2 i.v. days 1-4 V Etoposide (VP-16) 250 mg/m2 i.v. days 1-4

ABMT

Autologous bone marrow transplantation on day 7

Patients with resistant relapsed Hodgkin's disease47 C Cyclophosphamide 1.8 g/m2 i.v. daily (days 1-4) Carmustine (BCNU) 600 mg/m2 i.v. on day 5 V Etoposide (VP-16) 400 mg/m2 i.v. b.i.d. (days 1-3)

ABMT

Autologous bone marrow transplantation on day 7 (With/without radiation therapy)

Patients with resistant relapsed Hodgkin's disease67 Cyclophosphamide 1.8 g/m2 i.v. daily (days -7 to -4) Carmustine(BCNU) 600 mg/m2 i.v. on day -3 V Etoposide(VP-16) 400 mg/m2 i.v. b.i.d. (days -7 to -4)

ABMT

Autologous bone marrow transplant on day 0.

Patients with refractory Hodgkin's disease and non-Hodgkin's lymphoma84 (Maximum-tolerated dose = MTD) Cyclophosphamide 0.9 g/m2 i.v. b.i.d. (days -7 to -4) Carmustine(BCNU) 450 mg/m2 i.v. bolus on day -7 V Etoposide(VP-16) 250 mg/m2 i.v. b.i.d. (days -7 to -4)

ABMT

Unpurged autologous bone marrow transplant

Other treatments for Hodgkin's disease containing cyclophosphamide

CVPP59

Cyclophosphamide 300 mg/m2 i.v. on days 1 and 8 V Vinblastine 10 mg/m2 i.v. on days 1, 8 and 15

P 2 p.o.

Procarbazine 100 mg/m

on days 1 to 15

P 2 p.o.

Prednisone 40 mg/m

on days 1 to 15

NOTE:

Repeat the cycle every 28 days. Prednisone is given in cycles 1 and 4 only

14-year follow-up results:

CVPP24

NOTE:

CVPP CVPP

Repeat cycles every 42 days for a minimum of six cycles. Patients in CR after 6 or more cycles of

continue to receive

at 2-4- month intervals as maintenance therapy for a median period of 34 months.

NON-HODGKIN'S LYMPHOMA

Since the acute risks of multi-agent systemic chemotherapy include myelosuppression, possible hemorrhage, and infection, use of transplantation of bone marrow, peripheral stem cell support, various colony-stimulating factors,76,81 and pathology-specific antibiotics should be considered prior to chemotherapy, to speed up the patient's recovery.

Childhood N H L (Lymphoblastic and non-lymphoblastic lymphoma)

22,80

Induction phase of modified LSA2-L2

Cyclophosphamide 1.2 g/m2 i.v. day 1 Vincristine 2.0 mg/m2 i.v. (maximum dose 2.0 mg) days 3, 10, 17, and 24 Methotrexate 6.25 mg/m2 i.v. days 5, 31, and 34 Daunomycin 60 mg/m2 i.v. days 12 and 13 Prednisone 60 mg/m2 p.o. (maximum dose 60 mg/m2) days 3-30

COMP

Induction

Cyclophosphamide 1.2 g/m2 i.v. day 1 Vincristine 2.0 mg/m2 i.v. (maximum dose, 2.0 mg) days 3, 10, 17, and 24 Methotrexate 6,25 mg/m2 i.th. days 5, 31, and 34 Methotrexate 300 mg/m2 i.v. (60% of dose as i.v. push, 40% as 4-h infusion on day 12) Prednisone 60 mg/m2 p.o. (maximum dose 60 mg) days 3-30

COMP

Maintenance

Cyclophosphamide 1 g/m2 i.v. day 1 Vincristine 1.5 g/m2 (maximum dose 2.0 mg) i.v. days 1 and 4 Methotrexate 6.25 mg/m2 i.th. day 1 (excluded from first maintenance cycle) Methotrexate 300 mg/m2 i.v. (60% of dose as i.v. push, 40% as 4-h infusion) on day 15 Prednisone 60 mg/m2 p.o. (maximum dose 60 mg) days 1-5 (excluded from first maintenance cycle)

NOTE:

Repeat maintenance cycle every 28 days

Adult advanced-stage intermediate- or high-grade Non-Hodgkin's lymphomas:

CHOP

22,28,29,30,38

C Cyclophosphamide 750 mg/m2 i.v. on day 1 H Hydroxydaunorubicin (Doxorubicin) 50 mg/m2 i.v. on day 1

1. Oncovin (Vincristine) 1.5 mg/m2 i.v. (max.2 mg/m2) on day 1

2. Prednisone 100 mg/m2 p.o. on days 1 to 5

In a large phase III comparison of CHOP vs. third-generation regimens (m-BACOD, ProMACE- CytaBOM, MACOP-B), CHOP resulted in similar failure-free and overall survival rates with lower severe toxicity.30

LNH-84 Induction phase

Doxorubicin 75 mg/m2 i.v. on day 1 Cyclophosphamide 1.2 g/m2 i.v. on day 1 Vindesine 2 mg/m2 i.v. on days 1 and 5 Bleomycin 10 mg p.o. on days 1 and 5 Methylprednisolone 60 mg/m2 on days 1 and 5 Methotrexate 12 mg i.th. once per course

NOTE:

Courses are given every 15 days, or when polymorphonuclear neutrophils exceed 1500/uL. Total therapy (induction followed by consolidation and final intensification course) requires 8 months.

F-MACHOP2,37

Vincristine 0.5 mg/m2 i.v. at time 0 and at 12 hours on day 1 Cyclophosphamide 800 mg/m2 i.v. at 36 hours (i.e., middle of day 2) Fluorouracil 15 mg/Kg continuous i.v. infusion starting at 36 hours for 6 hours Cytarabine 1 g/m2 by continuous i.v. infusion for 6 hours immediately following 5-FU infusion Doxorubicin 60 mg/m2 i.v. at 48 hours (end of day 2) Methotrexate 500 mg/m2 by continuous i.v. infusion for 6 hours beginning at hour 60 (middle of day 3) Prednisone 60 mg/m2 orally from day 1 to day 14 Leucovorin 20 mg/m2 i.v. 18 hours after methotrexate infusion, and repeated every 12 hours for four doses NOTE: Prophylactic i.th. methotrexate, 12 mg total dose, plus cytarabine, 30 mg/m2 is given to patients considered at high risk of CNS infiltration (advanced stage, marrow involvement, less than 30 years of age) on day 10 of each course. A course is administered every 3 or 4 weeks for a total of 6 cycles. During the last three cycles, the dose of doxorubicin is reduced to 40 mg/m2 and that of methotrexate to 300 mg/m2.

PRO-MACE-CYTABOM22,28,30

Cyclophosphamide 650 mg/m2 i.v. on day 1 Doxorubicin 25 mg/m2 i.v. on day 1 Etoposide 120 mg/m2 i.v. over 60-minutes on day 1 Prednisone 60 mg/m2 p.o. on days 1 to 14 Cytarabine 300 mg/m2 i.v. on day 8 Bleomycin 5 mg/m2 i.v. on day 8 Vincristine 1.4 mg/m2 i.v. on day 8 Methotrexate 120 mg/m2 i.v. on day 8 Leucovorin rescue 25 mg/m2 orally every 6 hours for four doses beginning on day 9

NOTE:

Since this regimen is associated with an increased incidence of interstitial pneumonia with four related deaths reported, all patients now receive prophylactic trimethoprim-sulfamethoxazole as 2 tablets or 1 double-strength tablet twice daily.

NOTE:

The next cycle begins on day 22. At least 6 cycles, two cycles beyond a complete remission are given.

PRO-MACE-CYTABOM

chemotherapy is reported to produce at least 84% complete response (CR) in adult patients with diffuse aggressive lymphoma. The corresponding relapse rate (RR) is reported in these patients as 25%. The percentage of long-term survival is given as 69% after a 4.5-month duration of treatment.

COP-BLAM61

Cyclophosphamide 500 mg/m2 continuous i.v. infusion on day 1 Doxorubicin 50 mg/m2 continuous i.v. infusion on day 1 Vincristine 1 mg/m2 i.v. days 1-10 Prednisolone 40 mg/m2 p.o. days 1-10 Procarbazine 100 mg/m2 p.o. days 1-10 Bleomycin 10 mg/person continuous i.v. infusion on day 14 Lenograstim * 2ug/Kg/day s.c. when granulocyte count <1000 x 109/L Mean duration of administration of G-CSF for this trial was 5.4 days

*

Glycosylated recombinant human G-CSF

NOTE:

This regimen was repeated 6 times every 21 days

NOTE: Full dose of drugs for

70 years # 80% of full dose of cyclophosphamide and doxorubicin for ages 71-75 70% of full dose of cyclophosphamide and doxorubicin for ages 76-79 60% of full dose of cyclophosphamide and doxorubicin for ages 79-83

Localized low grade lymphoma (Working Formulation "B"):

Risk-adapted COP/CHOP-Bleo combined modality74 Cyclophosphamide 1000 mg/m2 i.v. on day 1 Vincristine 1.4 mg/m2 i.v. (max. 2.0mg) on day 1 Bleomycin 15 units total i.v. on day 1 Prednisone 60 mg/m2 p.o. daily for 5 days

Patients with extranodal involvement, bulky disease ($ 5cm), or LDH8: In addition to the above COP-Bleo

Doxorubicin 50 mg/m2 i.v. (max.450 mg/m2 or less if cardiac toxicity) on day 1 Cyclophosphamide9 750 mg/m2 i.v. on day 1

NOTE:

Bleomycin was not given to patients >60 years old, or to those with existing pulmonary toxicity. Therapy-related pulmonary toxicity led to removal of bleomycin. Both cyclophosphamide and doxorubicin were reduced by 20% following abdominal radiation.

NOTE: COP/CHOP-Bleo for 3 cycles

COP/CHOP-Bleo for 7 cycles IF

Initial chemotherapy

(Involved field) radiotherapy to supradiaphragmatic fields at a rate of 2 Gy per fraction to a total of 40 Gy in 4 weeks.

to a total of 10 cycles.

MULTIPLE MYELOMAS28

CYP + PRED

Cyclophosphamide 150 to 250 mg/m2 (500 mg maximum) i.v. or p.o. per week Prednisone 100 mg p.o. every other day.

M-2 (VMBCP)29,57

Vincristine 0.03 mg/Kg i.v. on day 1 Carmustine 0.5 mg/Kg i.v. on day 1 Cyclophosphamide 10 mg/Kg i.v. on day 1 Melphalan 0.25 mg/Kg p.o. for 4 days Prednisone 1.0 mg/Kg/day p.o. for 7 days, and then 0.5 mg/Kg/day p.o. for 7 days

NOTE:

Repeat the cycle every 35 days

VMCP alternating with VCAP V M C P

Vincristine 1.0 mg/m2 (maximum 1.5 mg) i.v. on day 1 Melphalan 6 mg/m2 p.o. on days 1 to 4 Cyclophosphamide 125 mg/m2 p.o. on days 1 to 4 Prednisone 60 mg/m2 p.o. on days 1 to 4

NOTE:

Alternate every 3 weeks with the V C A P regimen

V C A P

Vincristine 1.0 mg/m2 (maximum 1.5 mg) i.v. on day 1 Cyclophosphamide 125 mg/m2 p.o. on days 1 to 4 Doxorubicin 30 mg/m2 i.v. on day 1 Prednisone 60 mg/m2 p.o. on days 1 to 4

Salvage treatment for VAD-resistant multiple myeloma:

HyperCVAD23

Cyclophosphamide 300 mg/m2 (over 3 hrs) b.i.d. days 1 to 3 (total 1.8 g/m2) with at least 2 L oral fluids. Simultaneously, continuous infusion of 600 mg/m2/day mesna for 3 days.

hours after completion of cyclophosphamide:

Vincristine 2.0 mg continuous infusion over 48 hours Doxorubicin 50 mg/m2 continuous infusion over 48 hours Day 11: Vincristine 2.0 mg rapid i.v. injection Dexamethasone 20 mg/m2 p.o. as single morning dose for 5 days beginning on day 1, and for 4 days beginning on day 11 G-CSF 5 ug/Kg/day s.c. starting on day 6, to be repeated daily until granulocyte level >2000/uL

Between days 8 and 18:

Ciprofloxacin 500 mg p.o. b.i.d. Fluconazole 100 mg p.o. daily Acyclovir 300 mg p.o. t.i.d.

NOTE:

HyperCVAD

Patients received a second cycle of

, provided there had been a 50% reduction in myeloma protein.

Maintenance for responding patients:

Cyclophosphamide 125 mg/m2 p.o. b.i.d. for 5 days every 5 weeks Dexamethasone 20 mg/m2 each morning for 5 days every 5 weeks

NOTE:

Myeloablative treatment with autologous blood stem cell transplantation may be needed for persistent resistant disease or remission consolidation.

High-dose cyclophosphamide + GCS-F 6 PBPC 8 /Multiple myeloma35

NOTE:

Start of hyperhydration at least 12 hrs before CP. The treatment protocol for 4 g/m

CP consists of 4 doses of CP.

Myelomatosis49

ABCM

Adriamycin 30 mg/m2 i.v. on day 1 of each 6-week cycle BCNU 30 mg/m2 i.v. on day 1 of each 6-week cycle Followed on day 22 by Cyclophosphamide 100 mg/m2/day p.o. Melphalan 6 mg/m2/day p.o. NOTE: If a neutrophil count of 1.8 x 109/L and a platelet count of 80 x 109/L has not been reached within 5 weeks of the last block of chemotherapy, the patient is treated with the following CP-weekly regimen: Cyclophosphamide 300 mg/m2 i.v. weekly on alternate days with Prednisone 40 mg/m2 p.o. weekly on alternate days

LEUKEMIAS

22,28

Dosage and schedule variations within each drug regimen may be necessary, depending upon stage of disease and condition of patient. A method used to "clean" (purge) bone marrow from contaminating tumour cells prior to autologous transplantation in patients with acute nonlymphocytic leukemia, is the incubation of marrow with 4- hydroperoxycyclophosphamide,87 or mafosfamide L-lysine salt.60 Busulphan and total body irradiation combined with cyclophosphamide are frequently used as pretransplant regimen.70

CBV as a conditioning regimen for allogeneic bone marrow transplantation for patients with acute leukemia.

C Cyclophosphamide 1.5 g/m2/day i.v. on day 1 to day 4 B BCNU 300 mg/m2 i.v. on day 1 V Etoposide 100 mg/m2 i.v. every 12 hours for 6 doses

Allogeneic bone marrow transplant 88

from HLA-identical sibling donors.

Chronic Lymphocytic Leukemia (CLL):

NOTE:

CLL's are considered to be a heterogenous group of chronic B-cell disorders, now included in the low-grade (indolent) non-Hodgkin's lymphomas.

CVP

Cyclophosphamide 400mg/m2 p.o. on days 1 to 5 Vincristine 1.4 mg/m2 i.v. on day 1 Prednisone 100 mg/m2 p.o. on days 1 to 5

CHOP

C Cyclophosphamide 750 mg/m2 i.v. on day 1 H Doxorubicin (Hydroxydaunorubicin) 50 mg/m2 i.v. on day 1 O Vincristine (Oncovin) 1.4 mg/m2 i.v. on day 1

P 2 p.o.

Prednisone 100 mg

on days 1 to 5

COP

Cyclophosphamide 400 mg/m2 i.v. on day 1 Vincristine 1.0 mg/m2 i.v. on day 1 Prednisone 40 mg/m2 p.o. on days 1 to 10

Chronic Myelogenous Leukemia (CML)22

(Ineffective in acute blastic crises)

NOTE:

For patients under 50 years of age with an HLA-identical sibling, consider an allogeneic bone marrow transplant in the chronic phase.

Acute Myelogenous Leukemia (AML) (M0-M7) 22

Most centers suggest marrow transplantation for patients who have an appropriately matched HLA- compatible allogeneic sibling donor. Autologous marrow transplantation provides a potential transplant option for patients who lack a histocompatible donor. Whether ABMT offers an advantage over chemotherapy alone in children with AML in first remission is currently being assessed. DNA damage and repair in patients receiving high-dose (60 mg/Kg in the evenings of days 8 and 7 before transplant) cyclophosphamide and radiation(2 Gy TBI in the morning of days 5 to 0) must be assessed,31 to obtain a safe interval between cyclophosphamide and irradiation.

Acute Lymphoblastic (Stem Cell) Leukemia (ALL) in Children68

(Cyclophosphamide given during remission is effective in prolonging remission duration)

Adult Acute Lymphoblastic Leukemia (ALL) Induction with additional options:

Prednisone 40-60 mg/m2/day p.o. for 21 days Vincristine 1.4 mg/m2 i.v. days 1, 8, 15, and 22 Daunorubicin 45 mg/m2/day i.v. on days 1-3 or days 16-18 Cyclophosphamide 1 g/m2 i.v. on day 1 L-Asparaginase 5000 IU/m2/day i.m. for 10-14 days or 10000 IU/m2 s.c. weekly for 3 weeks Cytarabine (ara-C) 1-3 g/m2 i.v. over 4-6 hours and given every 12 hours for 4-8 doses

Maintenance Course C of the French Multicentre Study (PAME):

Etoposide 200 mg/m2 i.v. on day 1 Cyclophosphamide 600 mg/m2 i.v. on day 1 Prednisone 40 mg/m2/day p.o. on days 15 to 21 Mercaptopurine 50 mg/m2/day p.o. on days 15 to 21 Reinduction Phase II of a German Multistudy Group: Cyclophosphamide 650 mg/m2 (maximum 1000 mg) i.v. on day 29 Cytarabine 75 mg/m2 i.v. on days 31 to 34 and 38 to 41 Thioguanine 60 mg/m2 p.o. on days 29 to 34

MYCOSIS FUNGOIDES (Advanced disease, Stages III, IVA, IVB)

Combined topical and systemic therapy after initial conservative topical treatment failed42: Total electron-beam radiation therapy, using rotating dual fields of between 3000 to 3200 cGy total dose to the skin for 8 to 12 weeks (skin tolerance). During the above therapy, the following 21-day cycles of parenteral combination chemotherapy were added: Cyclophosphamide 500 mg/m2 i.v. on day 1 Doxorubicin 50 mg/m2 i.v. on day 1 Etoposide 100 mg/m2 i.v. on days 1 to 3 Vincristine 1.4 mg/m2 (maximum 2 mg) i.v. on day 1 NOTE: A total of 8 cycles for patients with stage III and IVA A total of 16 cycles for patients with stage IVB (visceral disease), doxorubicin was omitted from the regimen after a cumulative dose of 450 mg/m2 was reached, and cyclophosphamide was then increased to 750 mg/m2

Other treatment combinations in addition to topical therapy:

(In advanced disease, the polychemotherapy addition may not significantly improve the outcome)

CHOP, COP, CVP (See pp. 24 for regimen detail)

FREQUENTLY RESPONSIVE SOLID MALIGNANCIES

NEUROBLASTOMA (In patients with disseminated disease, Stages III, IV & IV.S)

Combination chemotherapy regimen (myeloablative therapy included) with or without surgery and/or radiation therapy in children with disseminated neuroblastoma, included cyclophosphamide for both BMT conditioning and as regimen component, vincristine, doxorubicin, cisplatin, melphalan, vindesine, etoposide, teniposide and rescue with either allogeneic or autologous bone marrow.

The CVD regimen (cyclophosphamide, vincristine, dacarbazine) has been found active in advanced neuroblastoma, producing responses in 80% of children with metastatic disease.4 It should be noted that, based upon the neuroblastoma results, the CVD regimen has successfully been used in the treatment of advanced, malignant pheochromocytoma after optimization of antihypertensive therapy. Treatment strategy comparison was made, based upon the recognition that both tumours are neuroendocrine with similar clinical and biologic characteristics. Treatment of neuroblastoma with intraspinal extension (NBL 90/SIOP):64 4 alternating courses (AB) prior to surgery (removal of dumbbell neuroblastoma tumour), and 2 alternating courses postoperatively: Each course once every 21 days

Course A:

Carboplatin 200 mg/m2 i.v. per day x 3 days Etoposide (VP-16) 150 mg/m2 i.v. per day x 3 days

Course B:

Cyclophosphamide 300 mg/m2 p.o. or i.v. per day x 5 days Vincristine 1.5 (max 2.0 mg) mg/m2 i.v. per day on days 1 and 5 Doxorubicin 60 mg/m2 i.v. on day 5

Neuroblastoma CVD and CVDD regimen:27 Cyclophosphamide 750 mg/m2 i.v. on day 1 Vincristine 1.5 mg/m2 i.v. on day 5 (maximum dose 2.0 mg) Dacarbazine (DTIC) 250 mg/m2/day i.v. days 1 to 5

NOTE:

This regimen was repeated every 22 days whenever possible.

Cyclophosphamide 750 mg/m2 i.v. on day 1 Vincristine 1.5 mg/m2 i.v. on day 5 (maximum dose 2.0 mg) Dacarbazine (DTIC) 200 mg/m2/day i.v. days 1-5 Doxorubicin (adriamycin) 40 mg/m2 i.v. on day 3

NOTE:

This regimen was repeated every 29 days whenever possible. Dose escalations for both cyclophosphamide and dacarbazine were allowed for.

OPEC75

Vincristine 1.5 mg/m2 i.v. bolus on day 0 Cyclophosphamide 600 mg/m2 i.v. bolus on day 0 Cisplatin (sequentially timed) 100 mg/m2 after 24 h prehydration on day 1 as bolus and followed by 10% mannitol diuresis Teniposide 150 mg/m2 (sequentially timed) Pheochromocytoma CVD regimen:4 Cyclophosphamide 750 mg/m2 i.v. on day 1 Vincristine l.4 mg/m2 i.v. on day 1 Dacarbazine l.4 mg/m2 i.v. on days 1 and 2

NOTE:

21-day cycle with either 1-week treatment delay, or appropriate dosage modifications for hematologic or neurologic toxicities. In the absence of significant hematologic toxicity, the dosage of cyclophosphamide and dacarbazine was increased by 10% each cycle until myelo-suppression was seen. All patients received their first treatment while hospitalized.

CARCINOMA OF THE BREAST

The following are standard and effective combination chemotherapy regimen, commonly used to treat breast cancer. Over 50% response rates in previously untreated patients are reported for CAF and CMF with/without additional drug components.

NOTE:

Age < 50 years or > 50 years, pre- or postmenopausal status, and negative or positive axillary nodules must be part of each chemotherapy regimen design, in addition to the condition, the hematologic-, hepatic- and renal profile of the patient.

NOTE: Limited data62 suggest that adjuvant therapy (FAC, CMF) should be considered in male patients with primary breast cancer. Cyclophosphamide 500 mg/m2 i.v. on day 1 Adriamycin (doxorubicin) 50 mg/m2 i.v. on day 1 5-Fluorouracil 500 mg/m2 i.v. on day 1

NOTE:

Regimen is given every 21 days

High-dose CAF

C 600 mg/m2 i.v. on day 1 A 60 mg/m2 i.v. on day 1 F 600 mg/m2 i.v. on day 1

NOTE:

CAF

Courses are repeated every 28 days for 4 courses. High-dose

produces neutropenia, one must anticipate.

Oophorectomy(O) plus CAF, metastatic breast cancer in premenopausal women26

O + CAF (1st cycle of CAF within 28 days of O) C 2 p.o.

100 mg/m

on days 1 to 14

A 30 mg/m2 i.v. on days 1 and 8 F 500 mg/m2 i.v. on days 1 and 8 NOTE: Each cycle restarted 29 days after the previous cycle (28 days). Cycles continued until 500 mg/m2 doxorubicin(A) were administered. Maintenance therapy for patients who had reached the maximum of 500 mg/m2:

C 2 p.o.

100 mg/m

on days 1 to 14

Methotrexate 40 mg/m2 i.v. on days 1 and 8 F 600 mg/m2 i.v. on days 1 and 8 Fluoxymesterone (substituting for long-term use of prednisone, due to ADRs) 10 mg b.i.d. p.o. on days 1 to 28

FAC40

5-Fluorouracil 500 mg/m2 i.v. on days 1 and 8 Adriamycin(doxorubicin) 50 mg/m2 i.v. on day 1 Cyclophosphamide 500 mg/m2 i.v. on day 1

NOTE:

Repeat cycle every 21 days

CMF Adjuvant11

< 60 years

C2 p.o.

yclophosphamide 100 mg/m

on days 1 to 14

Methotrexate 40 mg/m2 i.v. on days 1 and 8 5-Fluorouracil 600 mg/m2 i.v. on days 1 and 8 > 60 years

C2 p.o.

yclophosphamide 100 mg/m

on days 1 to 14

Methotrexate 30 mg/m2 i.v. on days 1 and 8 5-Fluorouracil 400 mg/m2 i.v. on days 1 and 8

NOTE:

22,50

Repeat cycle every 28 days. This regimen can also be presented as follows:

C 2 p.o.

100 mg/m

days 1-14

M (40-60) mg/m2 i.v. days 1 and 8 F (400-700) mg/m2 i.v. days 1 and 8 (P) (40 mg/m2) (p.o.) (days 1 to 14)

C 2 p.o.

100 mg/m

on days 1 to 14

M 40 mg/m2 i.v. on days 1 and 8 F 600 mg/m2 i.v. on days 1 and 8

NOTE:

This is referred to as "standard CMF" (Milan Group)

Doxorubicin followed by CMF12,19,83

(4 courses doxorubicin followed by 8 courses of CMF vs 2 courses CMF alternated with 1 course of doxorubicin for a total of 12 courses) Doxorubicin 75 mg/m2 i.v. bolus every 21 days for 4 courses

Beginning with course 5

Cyclophosphamide 600 mg/m2 i.v. day 1 and every 21 days for 8 courses Methotrexate 40 mg/m2 i.v. day 1 and every 21 days for 8 courses 5-Fluorouracil 600 mg/m2 i.v. day 1 and every 21 days for 8 courses

NOTE:

This regimen is suggested as adjuvant therapy for patients with resectable breast cancer with 4 or more positive axillary nodes. If the patient becomes too neutropenic or thrombocytopenic, a 1- or 2-week therapy postponement should be initiated.

CA or AC22,71

Cyclophosphamide 200 mg/m2 p.o. days 3-6 Doxorubicin (Adriamycin) 40 mg/m2 i.v. on day 1

NOTE:

A

Recycle every 3 to 4 weeks. Total doses of

should not exceed 450 mg/m

Doxorubicin (Adriamycin) 45 mg/m2 i.v. on day 1 Cyclophosphamide 500 mg/m2 i.v. on day 1

NOTE:

A

Recycle every 3 weeks. Toxicity is reported high. Total doses of

should not exceed 450 mg/m

RETINOBLASTOMA (Stage II to IV)22 Chemoreduction is often employed to reduce the tumour volume to an extent that allows for focal treatment (cryotherapy, thermotherapy, plaque radiotherapy) of tumour residues. Other clinical settings where chemotherapy is considered are a high risk for or presence of metastatic disease and extraocular extensions of the tumour. Combinations of cyclophosphamide and dactinomycin, and cyclophosphamide and doxorubicin have been associated with mixed or partial responses in patients with locally extensive, regional, or distant disease. Preirradiation chemotherapy has been used for children with extensive intraocular tumours. Primary concerns are preservation of patient's vision, inhibiting tumour progression along the optic nerve, and genetic counselling of patient and patient's family.

MALIGNANT NEOPLASMS OF THE LUNG

22,

Frequently responsive:

Small-cell lung cancer (SCLC)

Effective commonly used polychemotherapy:

CAV

Cyclophosphamide 1 g to 1.5 g/m2 i.v. on day 1 Adriamycin (Doxorubicin) 45 to 70 mg/m2 i.v. on day 1 (max. total dose 450 mg) Vincristine 1-2 mg/m2 (max. dose 2.0 mg) i.v. on day 1

NOTE:

Repeat cycle every 3 weeks for up to 6 cycles

CAV EP

alternating with

1 cycle of CAV at the lower of above doses with 1 cycle of EP every 3 weeks Etoposide 100 mg/m2 i.v. days 1-3 Platinum (Cisplatin) 25 mg/m2 i.v. days 1-3

CAVE

Cyclophosphamide 1 g/m2 i.v. on day 1 Adriamycin (Doxorubicin) 50 mg/m2 i.v. on day 1 Vincristine 1.5 mg/m2 i.v. on day 1 Etoposide 60 mg/m2 i.v. days 1-5

NOTE:

Repeat cycle every 3 weeks

CAE

Cyclophosphamide 1 g/m2 i.v. on day 1 Adriamycin (Doxorubicin) 45 mg/m2 i.v. on day 1 Etoposide 50 mg/m2 i.v. days 1-5

NOTE:

Repeat cycle every 3 weeks

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name:

Cyclophosphamide BP & USP

Chemical Name:

2-[Bis(2-chloroethyl)] amino tetrahydro-2H-1,3,2-oxazaphosphorine

2-oxide monohydrate

Other Names:

B 518, NSC 26271, CYP, ENDOXAN-ASTA

Chemical Structure:

Molecular Formula: 7

C

H15Cl2N2O2P .H2O

Molecular Weight:

279.10

Physical Properties:

Physical Form:

White, almost odourless crystalline powder

Solubility:

Soluble in water, slightly soluble in alcohol, sparingly soluble in ether

pH Values: 4.0 - 6.0 BP

(2% solution in water)

- 7.1 USP

(1% solution in water)

Melting Point: 49.5degC - 53degC BP

with gel-like decomposition at 53.5degC BP

COMPOSITION

The PROCYTOX (cyclophosphamide) 25 mg and 50 mg tablets have the same formulation, containing the following Non-Medicinal Ingredients (in alphabetic order): Calcium carbonate, Dibasic Calcium phosphate, Cellulose, Gelatin, Glycerin, Lactose, Magnesium stearate, Polyethylene glycol, Polysorbate, Povidone, Silicon dioxide, Starch (Corn), Sucrose, Talc, Titanium dioxide, Wax. PROCYTOX vials contain only the labelled amount of cyclophosphamide. There are no excipients.

STABILITY AND STORAGE RECOMMENDATIONS

The recommended storage temperature for the PROCYTOX dosage forms is 15-25deg C. The dosage forms should be protected from direct light. During transport or storage of PROCYTOX injection vials, temperature fluctuations can lead to melting of the active ingredient, cyclophosphamide. Vials containing melted substance are easily noticeable, since the powder becomes a clear or viscous yellow liquid (seen as droplets or a connected phase in the affected vials). Do not use vials with melted content.

RECONSTITUTED SOLUTIONS

The following solutions have been recommended as diluents for intravenous infusion: 5% dextrose USP in 0.9% sodium chloride USP 5% dextrose USP in sterile water for injection USP 0.9% sodium chloride USP Such solutions are chemically stable for 24 hours at 15-25degC, or 72 hours under refrigeration (4degC). Unless prepared under aseptic conditions, such solutions should be used within 8 hours after dilution. An oral elixir may be prepared by dissolving the PROCYTOX dry powder contents of the vials in "Aromatic Elixir USP" shortly before administration. This liquid oral formulation, if refrigerated at 4degC, should be used within 14 days. Solutions of PROCYTOX for parenteral use should be prepared by adding isotonic, sterile, Sodium Chloride Injection USP to the vial, and shaking the contents until dissolution and a clear and a clear solution is obtained PROCYTOX should not be reconstituted with benzyl alcohol-preserved diluent solution such as bacteriostatic sodium chloride when used in children or infants, due to toxicity concerns in this age group (i.e., gasping syndrome in infants). Further, PROCYTOX should not be reconstituted or diluted with benzyl alcohol-containing diluents, as benzyl alcohol may catalyse the decomposition of cyclophosphamide. Therefore, it is recommended to reconstitute PROCYTOX with isotonic, sterile, Sodium Chloride Injection USP.

HEATING SHOULD NOT BE USED TO FACILITATE DISSOLUTION

Solutions prepared with isotonic, sterile, Sodium Chloride Injection USP should only be used for a single dose administration, and any unused portion should be discarded (see SPECIAL INSTRUCTIONS).

PARENTERAL PRODUCTS

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

October 2003

Since it has been reported that immersion of a needle with an aluminum component into cyclophosphamide resulted in a slight darkening of the aluminum and gas production after a few days at 24degC with protection from light, it is recommended to avoid the use of utensils, needles or parts of infusion pumps made of aluminum in the presence of PROCYTOX.

SPECIAL INSTRUCTIONS

Cyclophosphamide (PROCYTOX) is cytotoxic, carcinogenic, mutagenic and teratogenic. Avoid ingestion, inhalation, or skin and eye contact. Mandatory washing of hands before and after using gloves must be advised. If necessary, consult the Company's Material Safety Data Sheet.

Personnel, regularly handling these agents should have frequent hematologic examinations (CBC), and frequently be screened for urine mutagenesis.

Work-practice guidelines for personnel dealing with and handling cytotoxic and hazardous preparations must be respected, to minimize unnecessary exposure to cyclophosphamide in physicians, nurses, pharmacists, and technicians. Appropriate Personal Protective Equipment (PPE) must be available in all areas where cyclophosphamide is handled. See the following table:

Preparation of PROCYTOX must take place in a Pharmacy or, in facilities where there is not a Pharmacy, in a Class II Type B or better, externally-vented biological safety cabinet. The biological safety cabinet should have airflow monitoring devices and should be certified at least annually. Only luer-lock connections should be used in the preparation of PROCYTOX.

Disposal cyclophosphamide

of

-contaminated clothing, gloves, utensils, broken glass etc. must be considered as hazardous waste. It must be deposited into a 4 mil thick polypropylene hospital trash bag (properly labelled), or be otherwise segregated and incinerated at above 1000degC.

Chemical inactivation should, if possible, be avoided, since it is often ineffective and may produce byproducts that are more mutagenic than the parent drug.

Spills:

Cleaning up immediately, and decontaminating areas of spills and breakage by experienced and well-protected personnel is of utmost importance. Contaminated areas including hood interiors must have clearly worded warning labels posted. It is suggested that spill kits be easily accessible, and include replacement hood filters, a respirator ("P3" filter, Manufacturer's current recommendation for cyclophosphamide powder spills), chemical splash goggles, at least 2 pairs of protective gloves, at least 2 sheets (31cm x 33cm/12" x 13") of absorbent material, 250 mL and 1 Liter spill-control pillows, a small scoop, spatula, forceps or tweezers to collect glass fragments, and at least two large polypropylene hospital trash bags 4 mil or thicker, or other cytotoxic drug waste-disposal bags, puncture- and leak-resistant waste container for sharp or breakable objects or spilled liquid, and warning sign (e.g., " Danger - Cytotoxic Agent Spill"). Absorbents should be incinerable.

AVAILABILITY OF DOSAGE FORMS

PROCYTOX (Cyclophosphamide Tablets, USP):

PROCYTOX (Cyclophosphamide for Injection):

Vials containing cyclophosphamide for reconstitution. 200 mg, 500 mg, 1000 mg, 2000 mg Single vials, and boxes of 10 Protect from direct light. Available in single vials, boxes of 10.

PHARMACOLOGY

Preclinical Pharmacology

The reported difference in intravenous and oral AUC values between man and mice is in line with several reports of appreciable species differences in cyclophosphamide (CYP) metabolism, thought to be primarily due to variations in hepatic microsomal metabolism.

In the rat, following a 200 mg/Kg i.p. cyclophosphamide injection, a plasma elimination t1/2 of 1.1 hours was reported, comparing to a mouse plasma elimination t1/2 of only 0.2 hours. In the rat, the tissue cyclophosphamide elimination t1/2 was largest in liver, lung and kidney. The highest tissue concentration was found in the kidneys. Cyclophosphamide is an effective agent against the B-16 melanoma in C57BL/6 mice. The effect is dose-related over a range of from 50 to 200 mg/Kg; the latter dose of 200 mg/Kg causes a 120% increase in the median survival time. 10 mg/Kg is required to kill 50% of the tumor cells in vivo with a tumor strain that has a doubling time of 1 day. Cyclophosphamide in animals inhibits immune phenomena, inflammatory processes, delayed hypersensitivity reactions, experimental allergic inflammatory disease, and defenses against infectious micro-organisms.

T O X I C O L O G Y

Acute Toxicity

The following lethality studies were undertaken in male and female CDF1 mice, using single or multiple i.v. cyclophosphamide dose regimen.

Intravenous LD50

was reported as 40 mg/Kg for dogs, 130 mg/Kg for rabbits, 160 mg/Kg for rats, and 400 mg/Kg for guinea pigs.

Oral LD50

for cyclophosphamide in mice after: in rats after:

h

780 mg / Kg ---

h

750 mg / Kg 720 mg / Kg

h

600-726 mg / Kg 235 mg / Kg

days

580 mg / Kg 142 mg / Kg

days

350 mg / Kg 94 mg / Kg

The 14-day LD50 for oral cyclophosphamide in dogs was reported as 44 mg/Kg. Subcutaneous 100 mg/Kg chloramphenicol prior to 300 mg/Kg or 200 mg/Kg i.p. cyclophosphamide in adult rats is capable of partially protecting against the toxic and lethal effects of cyclophosphamide. The efficacy of 50 mg/Kg i.p. cyclophosphamide in 150 to 200 newborn and adult Swiss male mice per experiment under depleted and supplemented condition of vitamin A (p.o. 100 and 250 IU/mouse/day) was scrutinized. Supplemental vitamin A helped to check progression of solid murine sarcoma 180 growth, and also increased the effectiveness of chemotherapy. Cyclophosphamide titration in mice appears to enhance survival following treatment with cyclophosphamide up to, but not exceeding 450 mg/Kg. Hematuria was very much lower in the titrated group, also lung damage was less in the titrated mice. Intraperitoneal injection of cyclophosphamide, acrolein and phosphamide mustard into mice was used, to determine, which of the metabolites is responsible for ovarian toxicity. Using follicle destruction, ovarian volume and uterine weight as toxicity parameters, the investigators found only phosphoramide mustard responsible for cyclophosphamide ovarian toxicity.

Chronic Toxicity

Studies, using rats that received up to 12 mg/Kg cyclophosphamide by stomach tube for 80 days, indicated that the highest dose produced a 75% mortality rate after 8 weeks. Leukopenia was observed in all animals after 4 weeks of treatment. A high incidence of hematuria and petechial hemorrhage was found in lungs, gastrointestinal tract and urinary bladder. Dogs receiving cyclophosphamide p.o. of up to 5 mg/Kg 5 days a week for 6 weeks, presented a reduction in body weight, leukopenia and limited hemorrhagic lesions in lymph nodes, bladder, brain, lung, gastrointestinal tract and renal pelvis. Severity of bone marrow changes was related to dosage. Chronic administration of toxic doses led to hepatic lesions manifested as fatty degeneration followed by necrosis. The intestinal mucosa was not affected. The threshold for hepatotoxic effects was 100 mg/Kg in the rabbit and 10 mg/Kg in the dog. The carcinogenic effect of cyclophosphamide was demonstrated not only in rats but also in mice. Cyclophosphamide is mutagenic in animals. Reproductive and teratologic toxicity of cyclophosphamide in animals is well documented.

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