Procytox

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 antitumor 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 t_½ and AUC of cyclophosphamide after a 5-day continuous infusion schedule of 300-400 mg/m²/day, were similar to the t_½ 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 µmoles/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.

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.

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.

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

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.

Each round, deeply biconvex, off-white, sugar-coated tablet contains: 53.5 mg cyclophosphamide monohydrate equivalent to 50 mg anhydrous cyclophosphamide. Nonmedicinal ingredients: calcium carbonate, cellulose, dibasic calcium phosphate, gelatin, glycerin, lactose, magnesium stearate, polyethylene glycol, polysorbate, povidone, silicon dioxide, starch (corn), sucrose, talc, titanium dioxide and wax. Blister packs of 10, boxes 100.

Each round, deeply biconvex, white to off-white, sugar-coated tablet contains: 26.7 mg cyclophosphamide monohydrate equivalent to 25 mg anhydrous cyclophosphamide. Nonmedicinal ingredients: calcium carbonate, cellulose, dibasic calcium phosphate, gelatin, glycerin, lactose, magnesium stearate, polyethylene glycol, polysorbate, povidone, silicon dioxide, starch (corn), sucrose, talc, titanium dioxide and wax. Bottles of 200.

Each vial contains: cyclophosphamide 200, 500, 1000 and 2000 mg. No excipients. Single vials. Protect from direct light.

Alopecia occurs commonly in patients treated with even low doses of cyclophosphamide. With large parenteral doses, considerable hair loss (5-30%, with possible total alopecia) is to be expected. The hair can be expected to grow back after or even during continued treatment; it may, however be different in texture and/or colour.

Skin rash occurs occasionally. Pigmentation of skin and changes in nails may occur.

A case of a variant of CHOP-associated erythrodysesthesia syndrome (identified as a variant of palmar-plantar erythema) related to high-dose cyclophosphamide has been reported.

Cardiotoxicity, which is uncommon at usual cyclophosphamide dosages, has been reported at high doses of between 120 and 180 mg/kg to as high as 270 mg/kg within a period of 4 to 6 days. This dosage range is usually part of an intensive polychemotherapy regimen, or is given in conjunction with transplantation procedures. This secondary cardiomyopathy may manifest as arrhythmias, ECG changes and/or LVEF (e.g., myocardial infarction). Cases of severe and sometimes fatal congestive heart failure have occurred within a few days after the first dose of a high-dose course of cyclophosphamide. Histopathologic examination revealed primarily hemorrhagic myocarditis. A fatal high-dose cyclophosphamide-induced cardiomyopathy, characterized by hemorrhagic myocardial necrosis has been reported.

There is evidence that the cardiotoxic effect of cyclophosphamide may be enhanced in patients who have received previous radiation treatment of the heart region and/or adjuvant treatment with anthracyclines or pentostatin. In this context, regular electrolyte monitoring is necessary and special caution is advised in patients with pre-existing heart disease.

Sudden weight gain, ECG abnormalities, dyspnea and/or other signs of congestive heart failure should be monitored. The antidiuretic effect, occasionally seen with cyclophosphamide alone, and as drug interaction with indomethacin (the latter manifesting itself as severe water intoxication-SIADH), may contribute to the cardiopulmonary pathology.

Pulmonary toxicity due to cyclophosphamide is a recognized entity. Interstitial pulmonary fibrosis, which can be fatal, has been reported with long-term high-dose cyclophosphamide. Careful monitoring is advised, since in some cases the discontinuance of the drug and administration of corticosteroids have failed to reverse this syndrome. In isolated cases, pneumonitis may develop.

Nausea and vomiting are common with cyclophosphamide treatment and are dose-dependent. Moderate to severe forms occur in approximately 50% of patients. Anorexia and, less frequently, abdominal discomfort or pain, diarrhea or obstipation, constipation and inflammatory conditions of the mucosa (mucositis), ranging from stomatitis to ulcerations may occur. There have been isolated reports of hemorrhagic colitis, oral mucosal ulceration (stomatitis), and jaundice occurring during therapy. These adverse events generally remit when cyclophosphamide is stopped.

Depending on the dose of cyclophosphamide administered, different degrees of myelosuppression may occur, involving leukocytopenia, thrombocytopenia, hypothrombinemia, and anaemia. It can commonly be expected that leukocytopenia with and without fever and the risk of secondary (sometimes life-threatening) infections will occur, as will thrombocytopenia associated with the higher risk of a bleeding event. The leukocyte and platelet nadirs are usually reached in week 1 and 2 of treatment. They usually recover within 3 to 4 weeks after the initiation of treatment. Anaemia will usually not develop until after several treatment cycles. Pancytopenia is a known ADR of cyclophosphamide in combination with, for instance, etoposide and cisplatin, where individual drug cause is difficult to identify. More severe myelosuppression is to be expected in patients who have been pre-treated with chemo- and/or radiotherapy and in patients with renal impairment. A combination treatment with other myelopsuppressive agents may require dose adjustments.

Leukopenia of less than 2000 cells/mm³ develops commonly in patients treated with an initial loading dose of the drug.

Thrombocytopenia nadirs occur within 10-15 days after administration.

The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infection.

Thrombocytopenia, hypothrombinemia, and anemia occasionally develops in patients treated with cyclophosphamide. These toxic effects can usually be reversed by reducing the drug dose or through interruption of treatment.

Nadir fever, headache, dizziness, diabetes mellitus, blurring of vision and myopia. Rare cases of rhabdomyolysis have been reported. Acute pancreatitis may occur in isolated cases. In rare cases, severe skin reactions like Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported under cyclophosphamide therapy. Cyclophosphamide may impair wound healing, which can be alleviated by supplemental vitamin "A"; monitoring the patient is necessary, to prevent a possible drug interaction.

There are certain complications, such as thromboembolism, DIC (disseminated intravascular coagulation), or hemolytic uremic syndrome (HUS), that may also be induced by the underlying disease, but that might occur with an increased frequency under chemotherapy that includes cyclophosphamide.

Carcinogenesis: As with cytotoxic therapy in general, treatment with cyclophosphamide involves the risk of secondary tumours and their precursors as late sequelae. The risk of developing urinary tract cancer as well as myelodysplastic alterations partly progressing to acute leukemias, or non-malignant disease in which immune processes are believed to be involved pathologically is increased. Urinary bladder malignancies have usually occurred in patients who previously had hemorrhagic cystitis. Animal studies demonstrate that the risk of bladder cancer can be markedly reduced by an adequate administration of mesna.

There have been isolated reports of hemorrhagic cystitis resulting in death.

Sterile hemorrhagic cystitis, which can become a severe to fatal condition, mainly due to long-term daily low-dose, or short-term high-dose cyclophosphamide, is thought to be secondary to the formation/concentration of the toxic metabolite acrolein during prolonged contact with the bladder epithelium. Changes in the efferent urinary tract may also occur. Hemorrhagic cystitis, microhematuria and macrohematuria are the most common dose-dependent complications of treatment with cyclophosphamide. Cystitis is initially abacterial; secondary bacterial colonization may follow. Reduction or interruption of cyclophosphamide, forced diuresis, hydration may limit the time of contact between the metabolite acrolein and the bladder epithelium. Prophylactic Mesna treatment is effective in many patients. Hematuria usually resolves spontaneously within a few days after interruption of cyclophosphamide therapy, but may persist for several months.

Cyclophosphamide-related non-hemorrhagic cystitis, edema of the bladder wall, suburethral bleeding, interstitial inflammation, and at times extensive fibrosis of the bladder with atypical cells in the urinary sediment have also been reported. A potential for sclerosis of the bladder wall also exists. Cryosurgery and other methods have been used in protracted cases.

Renal lesions (particularly in patients with a history of impaired renal function) are a rare side effect after high doses of cyclophosphamide. Interruption of therapy may, in most cases, resolve the lesion.

Second malignancy of the urinary bladder may develop, generally in patients who previously developed hemorrhagic cystitis, and may in some cases not be detected until several years after discontinuance of cyclophosphamide. Studies in animals have demonstrated that the risk of bladder cancer can be markedly reduced by an adequate administration of Mesna treatment.

Sterility in both sexes may result from cyclophosphamide treatment, depending on dose, duration of therapy, and state of gonadal function at time of treatment. By virtue of its alkylating mode of action, cyclophosphamide can be assumed to cause partially irreversible disturbances of spermatogenesis and the resulting azoospermia or persistent oligospermia. Ovulation disorders, that sometimes take an irreversible course, with the resulting amenorrhoea and lower levels of female sex hormones occur with a rarer frequency. Ovarian atrophy, fibrosis and complete absence of follicular structures are reported histologic features in some cyclophosphamide-treated women, where regaining reproductive function is unpredictable.

As a result of rapid cellular destruction (tumor lysis), especially in non-Hodgkin's lymphomas or leukemias, hyperuricemia may occur in some patients being treated with cyclophosphamide. Hyperuricemia may be minimized by adequate hydration, alkalinization of the urine, and/or administration of allopurinol. If allopurinol is decided upon, the patient must carefully be monitored to prevent severe cyclophosphamide toxicity (see Precautions, Drug Interactions). Cyclophosphamide-related hyperkalemia may also be due to tumorlysis.

A syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia and water retention has occurred in patients on high-dose cyclophosphamide therapy. Careful monitoring of this condition is advised.

Rare cases of disturbances of hepatic function have been reported that are reflected by an increase in the corresponding laboratory test values (AST, ALT, gamma-GT, alkaline phosphatase and/or bilirubin).

Veno-occlusive disease (VOD) is observed in approximately 15-50 % of the patients receiving high-dose cyclophosphamide in combination with busulfan or whole-body irradiation during allogenic bone marrow transplantation. By contrast, VOD is only rarely observed in patients with aplastic anaemia who are receiving high dose cyclophosphamide alone. The syndrome typically develops 1-3 weeks after the transplantation and is characterized by sudden weight gain, hepatomegaly, ascites and hyperbilirubinaemia. Hepatic encephalopathy may also develop. Known risk factors predisposing a patient to the development of VOD are pre-existing disturbances of hepatic function, hepatotoxic drug therapy concurrently with high-dose (chemo)therapy and especially when the alkylating agent busulfan is an element of the conditioning therapy.

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.

See Symptoms.