General principles of the use of cyclophosphamide in rheumatic diseases

INTRODUCTION — Cyclophosphamide (CYC), an alkylating agent, is one of the most potent immunosuppressive therapies available. It has been used extensively to treat severe manifestations of a variety of autoimmune and inflammatory diseases. Examples include organ-threatening manifestations of rheumatic diseases such as systemic lupus erythematosus (SLE), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome), Behçet syndrome, primary angiitis of the central nervous system, and isolated vasculitic neuropathy.

It is a prodrug that is converted to its active form in the liver and, to a lesser extent, in other organs. It can be administered either orally or intravenously. Oral administration usually corresponds to daily dosing and intravenous use to intermittent dosing (eg, every two to four weeks), but some exceptions exist. For example, extremely ill patients who are unable to ingest medications orally may rarely receive daily doses of CYC via the intravenous route at the same doses they would otherwise receive orally.

Although very effective, CYC has the potential for devastating toxicity both in the short and long term (even after the medication has been stopped). Concerns about such drug toxicity, especially malignancy, have restricted its use to patients with the most severe disease, or patients who are either intolerant of or unable to adhere to less toxic orally administered immunosuppressive drugs (eg, mycophenolate mofetil). Newer, short-term protocols using significantly reduced cumulative doses of CYC have reduced, but not eliminated, associated risks.

Two major aims govern the use of CYC:

●Prompt control of the underlying disease, to limit the extent and severity of damage

●Discontinuation of CYC as soon as possible and replacement with a less toxic alternative, to minimize the short- and long-term morbidity that often results from CYC itself

The pharmacology, administration, and monitoring of both oral and intravenous CYC will be reviewed here. The mechanism of action of CYC and other alkylating agents and the general toxicity of these drugs are discussed elsewhere (see "General toxicity of cyclophosphamide in rheumatic diseases"). The use of CYC for the treatment of specific rheumatic diseases is also discussed elsewhere. (See treatment sections of disease-specific topic reviews.)

PHARMACOLOGY — The metabolism and excretion of cyclophosphamide (CYC) are important issues related to its toxicity.

●Stability – CYC tablets should be stored in covered containers. Refrigeration is not necessary, although the drug may be unstable at temperatures exceeding 25ºC.

For intravenous use, CYC powder is reconstituted in sterile or bacteriostatic water. Reconstituted solutions should be refrigerated and infused within six hours unless bacteriostatic water is used. Reconstituted solutions may then be mixed with 50 to 150 mL of 5 percent dextrose, 0.45 percent or 0.9 percent saline, or lactated Ringer's solution for infusion. CYC is inactive as administered, reducing the risk of inadvertent subcutaneous infiltration.

●Absorption, metabolism, and distribution – Oral CYC is rapidly and almost completely absorbed. It is metabolized primarily in the liver to 4-hydroxy CYC and aldophosphamide (figure 1); the latter compound is then converted to the active metabolite phosphoramide mustard and the highly reactive aldehyde, acrolein, which is primarily responsible for bladder and cardiac toxicity. The appearance of these metabolites is delayed after the initial administration. Acrolein can be found in the urine as long as 24 hours after CYC administration. The active metabolites are highly protein-bound and distributed to all tissues including brain and cerebrospinal fluid. The active metabolites are assumed to cross the placenta and are known to be present in breast milk in small amounts [1]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.)

●Elimination – Both active and inactive metabolites are primarily excreted unchanged in the urine, with elimination complete by 48 hours. Consequently, the dose of CYC should be adjusted according to the degree of renal dysfunction [2,3]. (See 'Intermittent (pulse) cyclophosphamide' below and 'Daily oral cyclophosphamide' below.)

CONTRAINDICATIONS — The following conditions represent relative contraindications to the use of cyclophosphamide (CYC):

Active infection — Because of the risk of neutropenia, CYC therapy should be avoided in the presence of active systemic or potentially life-threatening infection. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Infection'.)

Neutropenia — CYC use in neutropenic patients should be avoided, unless the neutropenia is believed to be immune-mediated. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Hematologic toxicity'.)

Pregnancy and conception — CYC, like other alkylating agents, is teratogenic and is generally contraindicated in the first trimester of pregnancy. In females of childbearing potential, highly effective contraception and appropriate pregnancy testing are indicated. In life-threatening circumstances, particularly in the second and third trimesters of pregnancy, the use of CYC may be appropriate for severe disease when an effective and safer alternative is unavailable [4]; however, other agents are typically preferred when possible. Late pregnancy exposure to CYC may not increase the risk for adverse fetal effects. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

In addition, because CYC can cause genetic changes in sperm, several groups recommend that males taking CYC avoid conceiving a pregnancy while taking the medication and in the 90 days following treatment. Because CYC may cause long-term azoospermia, sperm cryopreservation is recommended prior to CYC initiation. (See 'Infertility risk' below and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases", section on 'Cyclophosphamide'.)

Inadequate contraception — Some patients may be too ill to institute contraception at the time of initial drug administration, in which case the issue must be addressed as soon as possible. Even patients with severe rheumatic disease are fertile and can conceive without contraception. Patients should be carefully, clearly, and repeatedly counseled about avoiding conception with appropriate documentation while on CYC. (See "Contraception: Counseling and selection".)

Lactation — Patients should not breastfeed following CYC treatment. Active and/or toxic metabolites were found in 3 females with measured milk samples up to 21 days after infusion [1,5,6]. Two infants developed neutropenia after breastfeeding soon after maternal CYC therapy [1,7-10]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.)

Prior history of hemorrhagic cystitis — CYC therapy is associated with both hemorrhagic cystitis and bladder cancer. The major cause of bladder toxicity is the exposure to the metabolite acrolein, which can appear in the urine for up to 24 hours after CYC administration. (See 'Pharmacology' above.)

The occurrence of hemorrhagic cystitis increases the risk of developing secondary bladder cancer and is traditionally considered a contraindication to further administration of CYC, particularly if alternative therapies are available. This common practice is not strongly evidence-based and it is arguable that, in the face of severely active disease with a remote or poorly documented history of hemorrhagic cystitis and no equally effective alternate therapy, use of pulse intravenous (but not daily oral) CYC may be reasonable.

The risk of bladder toxicity secondary to CYC use is discussed in detail elsewhere (see "General toxicity of cyclophosphamide in rheumatic diseases" and "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients"). The prevention of drug-induced bladder toxicity associated with CYC is discussed below. (See 'Prevention of drug-induced cystitis' below.)

PRETREATMENT EVALUATION — Prior to treatment with cyclophosphamide (CYC), we routinely address the following (table 1):

Drug interactions — CYC is a prodrug that is converted to its active form (4-hydroxycyclophosphamide) by several cytochrome P450 enzymes in the liver, notably CYP2B6. CYP2B6 is highly polymorphic, which may account for some of the pharmacokinetic variability seen among patients [11]. In addition, other drugs may alter the metabolism of CYC, which may impact the therapeutic effects. Thus, an assessment for drugs that alter the pharmacokinetics or toxic effects of CYC must be considered prior to administration.

Examples of potentially significant CYC drug interactions include:

●Drugs that alter activity of hepatic enzymes – Drugs that induce hepatic microsomal enzymes including CYP2B6 (eg, carbamazepine, barbiturates, phenytoin, rifampin) may accelerate the metabolism of CYC into its active metabolites and thus increase both the pharmacologic and toxic effects [12,13]. Conversely, drugs which inhibit the hepatic microsomal enzymes (eg, clopidogrel, desipramine, paroxetine, sertraline) slow the conversion of CYC to active metabolites, and thus may decrease both therapeutic and adverse effects.

●Succinylcholine – CYC reduces plasma pseudocholinesterase activity; thus, coadministration or subsequent use of succinylcholine may lead to prolonged neuromuscular blockade [14-16]. Anesthesiologists should be aware of recent CYC treatment prior to administering succinylcholine.

●Allopurinol – Allopurinol appears to increase systemic exposure of CYC's toxic metabolites by altering liver metabolism or renal excretion; studies of this interaction have yielded inconsistent results [17-19].

●Anticholinergic agents – Tricyclic antidepressants and other anticholinergic agents delay bladder emptying and may lead to prolonged bladder exposure to acrolein.

Patients receiving CYC should have their medication regimen analyzed carefully for potential drug interactions, particularly when initiating and adjusting therapy; this may be done using the drug interactions program included within UpToDate.

Reproductive health counseling

Infertility risk — Patients with childbearing potential should receive counseling prior to treatment with CYC about the significant risk of infertility, and of premature menopause (primary ovarian insufficiency [POI]) in females. Whenever possible, patients interested in having children should meet with a reproductive endocrine and infertility specialist prior to therapy with CYC.

●Males – Cryopreservation of ejaculated semen is usually the preferred fertility-preserving measure in males. This should be completed prior to initiation of CYC as the risk for genetic anomalies within sperm is highest in the one to two weeks following CYC dosing. If the sample is not collected prior to CYC treatment, some recommend delaying sample collection to 6 to 12 months following CYC completion [20,21]. As many samples as is feasible are collected (typically one to six samples); given current advanced reproductive health technology, even limited sperm numbers with poor morphology can often be used to fertilize an egg. A sperm bank can generally be identified by contacting a local reproductive endocrinologist or urologist, and samples can often be collected by appointment prior to consultation with a specialist. If the patient is not able to ejaculate, urologists can surgically extract sperm. (See "Effects of cytotoxic agents on gonadal function in adult men" and "Intracytoplasmic sperm injection" and "Treatments for male infertility".)

●Females – Female patients may be offered cryopreservation of embryos or oocytes, although undergoing egg harvesting is often impractical in seriously ill patients. For female patients who are acutely ill and cannot access, afford, or medically tolerate cryopreservation of embryos or oocytes, the authors of this topic use a gonadotropin-releasing hormone (GnRH) agonist as an attempt to preserve fertility through ovarian suppression. In such cases, we give a GnRH agonist 10 to 14 days prior to the initial, or more commonly due to the urgency of CYC treatment, 10 to 14 days prior to the second CYC dose. In addition, we offer GnRH agonist to female patients who wish to preserve their own reproductive function and/or wish to not develop premature ovarian insufficiency. Dosing of the GnRH agonist on the day of CYC dosing is avoided because the initial dose of GnRH agonist typically induces an overstimulation of ovarian follicles and may increase the degree of ovarian damage if coincident with CYC dosing. The authors use either 3.75 mg of leuprolide every 4 weeks or 11.25 mg of leuprolide dosed every 12 weeks.

Limited data support the use of GnRH agonists in patients with rheumatic disease. A meta-analysis indicated that patients who received GnRH with CYC were more likely to have preservation of ovarian function (94.6 versus 58 percent, odds ratio 10.3, 95% CI 4.8-36.3) [22]. Pregnancy rates also appeared higher with GnRH agonist use (22 in 103 patients versus 6 in 75 patients). However, the quality of these data are low and thus the efficacy of GnRH agonists remains controversial [23]. Other experts, including other UpToDate contributors, do not use GnRH agonists for fertility preservation. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Role of GnRH agonist'.)

The likelihood of ovarian toxicity rises with increasing age of the patient and the cumulative dose of CYC received [24,25]. In breast cancer patients, cumulative doses of approximately 20 g of CYC for females in their twenties, 10 g CYC for females in their thirties, and 5 g for females in their forties were associated with a 50 percent risk of POI [26]. (See "Overview of side effects of chemotherapy for early-stage breast cancer", section on 'Risk factors'.)

Treatment regimens for lupus nephritis designed to decrease CYC exposure, such as the doses used in the Euro-lupus trial, which employed a cumulative CYC dose of only 3 g, are associated with correspondingly much lower rates of premature ovarian failure [27]. Not all females receiving this lower dose of CYC require GnRH-agonist cotherapy. The authors take into consideration the age of the patient, their future pregnancy goals, and the expected cumulative dose of CYC when deciding whether to initiate GnRH-agonist therapy.

Contraception — Female patients must be counseled about the need for effective contraception during and for three to six months after cessation of CYC administration. Even if menses stop while receiving CYC, patients should not assume that they are unable to conceive. Long-acting reversible contraceptives (LARC), including the intrauterine device (IUD) and implantable progesterone, are the most effective forms of contraception; the authors encourage LARC options for all female patients needing more than three months of CYC infusions. The approach to contraception in females with systemic diseases such as systemic lupus erythematosus (SLE) is presented in separate topics. (See "Approach to contraception in women with systemic lupus erythematosus", section on 'Long-acting reversible contraception' and "Contraception: Counseling and selection", section on 'Special populations'.)

Laboratory and clinical testing — We typically perform the following studies prior to CYC therapy:

●Complete blood count (CBC) with differential.

●Liver function tests, albumin.

●Creatinine, urinalysis.

●Serologic testing for hepatitis B and C infection.

●Screening for latent tuberculosis with tuberculin skin test (TST) or interferon-gamma release assays (IGRAs).

●Screening for cervical cancer and human papilloma virus (HPV) infection in females. All females with SLE, but especially those with prior CYC therapy, are at high risk for developing cervical dysplasia [28-30]. (See "Screening for cervical cancer in patients with HIV infection and other immunocompromised states", section on 'Immunosuppressed patients without HIV'.)

Prophylaxis for Pneumocystis jirovecii pneumonia infection — The immunosuppressive effects of CYC, especially when combined with corticosteroids or other immunosuppressive agents, increase the risk of developing of opportunistic infections, particularly infection with Pneumocystis jirovecii (carinii). Regardless of the route of administration, the authors provide P. jirovecii prophylaxis for all patients on CYC; however, this practice is best supported in individuals who are also on a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer, or who have leukopenia, and/or ANCA-associated vasculitis [31-33].

The benefit of P. jirovecii prophylaxis was shown in a meta-analysis of 13 studies of non-human immunodeficiency virus (HIV) immunocompromised patients, in which antibiotic prophylaxis reduced the risk of infection by 85 percent [34]. A common prophylactic strategy for P. jirovecii is trimethoprim-sulfamethoxazole (TMP/SMX; either one single-strength tablet daily or one double-strength tablet three times/week) (table 2). Because TMP/SMX is removed by hemodialysis, the medication should be administered after dialysis in patients on renal replacement therapy.

In patients who are allergic to either component of TMP/SMX, alternative regimens that can be used include atovaquone, dapsone with or without pyrimethamine, and monthly aerosolized pentamidine and are discussed separately (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'). Patients with SLE who have not previously demonstrated tolerance of TMP/SMX can be given an alternative drug such as atovaquone 1500 mg/day because of reports of a higher incidence of adverse reactions with sulfonamides in this population. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Issues with specific therapies'.)

Prevention of drug-induced cystitis — In addition to using the shortest possible course of CYC to reduce overall CYC toxicity, the following steps have been associated with a marked reduction of CYC-induced bladder toxicity:

●Use of intermittent CYC dosing instead of daily oral CYC dosing whenever possible. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Toxicity'.)

●Vigorous hydration during the use of CYC. Patients treated with daily CYC should maintain consistent intake of fluid on the order of several extra glasses of water a day (see 'Administration of oral CYC' below). For patients receiving bolus CYC, oral hydration for 24 hours before and after administration is combined with intravenous hydration at the time of administration (see 'Administration of intermittent CYC' below). Although vigorous hydration is regarded as a standard of care for bladder protection, it has never been formally evaluated in studies using CYC for the treatment of rheumatic diseases. Consider including diuresis in patients with renal or cardiopulmonary disease to avoid volume overload during therapy.

●Use of Mesna. There are no established guidelines for the use of Mesna (2-mercaptoethane sodium sulphonate) for the prevention of bladder toxicity secondary to CYC for the treatment of rheumatic diseases, and practice patterns vary among clinicians. The variation in practice is largely reflected by the lack of direct evidence for the efficacy of Mesna to prevent cystitis in patients receiving CYC for rheumatic diseases. Mesna is a thiol compound that inactivates acrolein in the urine to minimize the risk of bladder toxicity from alkylating agents CYC and ifosfamide (see "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients", section on 'Mesna'). Randomized trials have demonstrated efficacy of Mesna in reducing the risk of bladder injury in cancer patients receiving ifosfamide and high-dose CYC [35-37]. However, it is not clear whether these findings are applicable to rheumatic diseases, in which the cumulative dose of CYC is much lower and the routes of administration vary [38-40]. A retrospective study with over 1000 patients treated with CYC for rheumatic diseases found a similar incidence rate of 1 to 2 percent of hemorrhagic cystitis in patient groups concomitantly treated with or without Mesna [40]. The risk of hemorrhagic cystitis increased with higher cumulative CYC doses.

Many clinicians do not use Mesna based on the probable lower dose of CYC used for rheumatic disease, and correspondingly lower risk of hemorrhagic cystitis. However, it is not always possible to identify patients prospectively who may require repeated treatments of CYC and who may receive a subsequently higher cumulative dose of CYC. Thus, our authors use Mesna in patients receiving intravenous CYC based on its favorable safety profile and potentially protective effect. Dosing regimens are described below. (See 'Administration of oral CYC' below and 'Administration of intermittent CYC' below.)

Patients who incompletely empty their bladders are at increased risk of bladder toxicity. If there is a clinical concern, a bladder ultrasound should be performed and if there is a high post-void residual, use of Mesna is also appropriate for such patients.

Occasionally, patients develop allergic rashes after Mesna, requiring its use to be discontinued [41]. In our experience, patients who develop allergic reactions after receiving Mesna and CYC are much more likely to have reacted to the Mesna rather than CYC, although allergic reactions to CYC have been reported [42].

●Use alternative agents to CYC (when possible) in patients who have urinary retention due to the likelihood of increased exposure to toxic metabolites, particularly with daily administration. In our institution, two episodes of severe hemorrhagic cystitis, one fatal, have occurred in intensive care unit patients with reduced urine output and urinary retention.

Immunization requirements — We advise that all patients receive appropriate immunizations prior to the institution of CYC (table 3). Appropriate immunizations should also include coronavirus disease 2019 (COVID-19) vaccination. Additional considerations regarding the COVID-19 vaccine and timing of the administration for patients on CYC are discussed in detail separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

INTERMITTENT (PULSE) CYCLOPHOSPHAMIDE — Intermittent cyclophosphamide (CYC), usually administered intravenously every two or four weeks, is the most common approach for CYC treatment. One of the principal reasons for using intermittent CYC is concern about the long-term complications of daily oral therapy. If administered over the same time period, daily oral dosing results in a several-fold higher cumulative dose of CYC than intermittent CYC. Moreover, with intermittent pulses (eg, monthly), the bladder is exposed to acrolein for only one or two days each cycle, rather than every day.

A detailed discussion of the dosing regimens for intravenous CYC are presented in the disease specific topics. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Cyclophosphamide' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen'.)

Drug dose for intermittent CYC — Drug dosing for intravenous CYC can vary depending on the specific disease as well as provider experience and practice style. However, there are some general principles regarding dosing of CYC for various systemic rheumatic diseases, which we present below. More specific dosing regimens for the management of focal or diffuse lupus nephritis, which differs somewhat from below, are discussed in detail in a separate topic. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen'.)

●Initial dose – Selection of the initial dose of CYC for intravenous infusion for treatment of most of the vasculitides is based upon estimated body surface area (BSA) expressed in square meters (m²) and is further adjusted for renal function as estimated by a calculated creatinine clearance, advanced age, and obesity. Studies of and guidelines for intermittent CYC administration in breast cancer and other malignancies support treatment according to total rather than ideal body weight and suggest that this practice does not increase the incidence of infection [43]. The authors use total rather than ideal body weight in calculating initial bolus CYC doses for patients who are obese, but they try not to include body weight gained from fluid retention in patients with nephrotic syndrome. Since the ratio of ideal to actual body weight varies up to threefold in rheumatic disease patients, the choice of approach may have important implications.

In patients with normal renal function, the recommended initial dose of intermittent CYC is typically in the range of 500 to 750 mg/m² of BSA, with a maximum dose of 1200 mg per dose. A lower maximum dose of 1000 mg per dose is used for lupus nephritis. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

As a general rule to diminish the risk of toxicity, the initial dose of CYC should be reduced to 500 mg/m² BSA in patients who are at high risk for infection or older adults (eg, age greater than 70 years or if the estimated creatinine clearance is less than 40 mL/minute). Recommendations for dose adjustment in patients with more severe renal dysfunction are varied and not evidence-based. In the setting of renal failure, the extent of dose reduction may also be influenced by the acuteness and severity of the disease. Specific dose adjustments for altered kidney function are provided elsewhere. (See Cyclophosphamide drug information "Dosing: Kidney Impairment: Adult").

●Subsequent doses – Subsequent doses are adjusted based upon the patient's response to therapy and the nadir of the white blood cell count. The nadir of the lymphocyte count is usually at day 7 and the granulocyte count at day 14 [44]. For patients receiving CYC every four weeks, we routinely check complete blood counts (CBC) for the purpose of dose adjustment around day 10 as well as on the day of the subsequent pulse to be sure there was no significant residual bone marrow suppression from the previous dose. Most CYC protocols are administered for three to six months, after which patients are typically transitioned to another immunosuppressive agent with a lower risk of toxicity. As an example, patients receiving a CYC-based induction regimen for the treatment of granulomatosis with polyangiitis (GPA) may be transitioned to methotrexate after three to six months. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)

If the leukocyte nadir after the first administration of CYC is less than 3500/mm³ and/or the absolute neutrophil count is less than 1500/mm³, the dose at the next infusion should be reduced by 20 to 25 percent. If, on the other hand, the total white cell nadir is greater than 4000 per mm³ and if the patient has not encountered significant toxicity or achieved a remission, the CYC dose at the next infusion may be increased by 20 to 25 percent. Some experts recommend a maximum dose of 1 g/m² BSA; however, this dose limit may be too low, particularly if calculations are based on lean body weight.

Administration of intermittent CYC — In patients who are stable, intermittent intravenous CYC can be administered safely in the outpatient setting. Exceptions should be made for patients with heart failure or severe pulmonary hypertension (who may not tolerate the required pretreatment hydration well), those with severe nephrotic syndrome (who may be unable to maintain brisk urine outputs), and those who, for reasons of frailty, may tolerate even moderate nausea poorly. The aggressive use of diuretics and bladder irrigation through three-way Foley catheters are more feasible in inpatients. Even in the outpatient setting, however, intravenous fluids, antiemetics, and Mesna may be used to prevent toxicities commonly associated with CYC.

●Hydration – Patients must be hydrated adequately before, during, and immediately after the intermittent CYC infusions. Patients receiving intermittent CYC in the outpatient setting should receive one liter of intravenous fluid (eg, 0.45 or 0.9 percent saline) over a two- to four-hour period before the infusion. The choice of fluid is dictated by the relative risks of salt loading worsening edema in patients with renal disease or incipient congestive heart failure versus the occasional occurrence of hyponatremia due to SIADH (syndrome of inappropriate antidiuretic hormone secretion) after CYC administration. In our experience, using half normal saline is a reasonable compromise. CYC is usually infused over one hour. After the administration of CYC, all patients should be instructed to drink at least one liter of fluid every six to eight hours for 24 hours afterwards, and to void as frequently as possible. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Hyponatremia due to SIADH'.)

●Antiemetics – Intermittent intravenous CYC is moderately emetogenic, and recommended agents are discussed in detail elsewhere (see "Prevention of chemotherapy-induced nausea and vomiting in adults"). Adequate prevention of nausea and vomiting during and for the first 24 to 48 hours after the administration of the first dose of intravenous CYC helps prevent anticipatory emesis, which is a conditioned response of developing nausea during chemotherapy that can persist with subsequent treatments. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Anticipatory emesis'.)

●Use of Mesna – As described above, when using intermittent pulses of CYC, the authors administer Mesna concomitantly (see 'Prevention of drug-induced cystitis' above). There is no clearly defined strategy for administration. One method is to administer half the total Mesna dose intravenously 30 minutes before the CYC infusion, and the other half of Mesna is given after the CYC infusion (either intravenously or orally).

Monitoring of intermittent CYC dosing — In addition to the blood counts discussed above, renal function, urinalysis, and liver function tests are monitored at least monthly. (See 'Administration of intermittent CYC' above and 'Monitoring of oral CYC dosing' below.)

DAILY ORAL CYCLOPHOSPHAMIDE — Oral cyclophosphamide (CYC) remains an important treatment for life-threatening manifestations of systemic vasculitis. Oral CYC is available in 25 and 50 mg tablets, and can be taken either on an empty or full stomach (table 4).

Drug dose for oral CYC

●Initial dose – The standard starting dose of daily CYC in a patient with normal kidney function is typically 1 to 1.5 mg/kg per day titrating up by 0.5 mg/kg per day every week up to 2 mg/kg per day (maximum dose 200 mg). Unfortunately, many patients on CYC have diseases associated with decreased renal function. In such settings, the dose of CYC must be modified (table 5). Conversely, doses lower than 1 mg/kg per day may not be effective in patients with normal renal function [45].

●Dose modification – The dose of daily CYC should be modified in the following circumstances:

•Resistant disease – In patients with resistant disease, cautious upward titration of CYC dose may be attempted. Clinicians must be as certain as possible that disease "refractoriness" is truly due to active disease rather than to irreversible damage (the latter will not respond to more CYC) or poor adherence (where increasing the dose may lead to unexpected toxicity). In prescribing CYC, the authors do not exceed 2.5 mg/kg per day of CYC; higher doses are associated with substantially increased risks of hematologic toxicity, opportunistic infections, and drug-induced cystitis.

•Renal insufficiency – Subsequent doses of CYC must be adjusted downward if renal function worsens during the treatment course (table 5). Conversely, marked improvement in renal function may allow for increased doses.

A moderate quantity of CYC is removed from circulation at dialysis. Thus, a supplemental dose of CYC should be given after a hemodialysis session if the dialysis patient received their usual daily dose of CYC prior to the session. The supplemental dose is generally equal to 50 percent of their usual daily dose.

•Obesity – Dose adjustment for obesity is controversial in patients receiving monthly intravenous CYC (see 'Drug dose for intermittent CYC' above), and there are no clear guidelines for oral administration. Some experts recommend that the initial dose should be adjusted based upon an approximation of the ideal body weight rather than the actual patient weight [2].

Administration of oral CYC — Oral CYC can be administered safely in the outpatient setting in stable patients.

●Hydration – CYC tablets should be administered in the morning and the patient advised to drink liberal quantities of fluid throughout the day (eight 8-ounce glasses of water or 2 liters are recommended). Patients should also attempt to empty their bladders before going to sleep. These measures decrease the time the bladder is exposed to the toxic metabolite acrolein.

●Use of Mesna – We do not use Mesna for patients on oral CYC based on the expense, inconvenience, terrible taste, and lack of evidence for a protective effect. Daily oral administration of Mesna during daily CYC administration has been reported, but we and most other centers do not use daily Mesna [46]. (See 'Prevention of drug-induced cystitis' above.)

Monitoring of oral CYC dosing — For patients on CYC, regular and frequent laboratory evaluations are required to screen for bone marrow toxicity, monitor renal function, and avoid major drug-induced bladder complications.

●Blood counts and differential – Complete blood counts (CBC) with differential should be obtained frequently. As an example, we repeat cell counts and differential every two weeks for as long as the patient is on CYC. Some clinicians may measure a CBC and differential every four weeks once patients have been on a stable dose of oral CYC. Total white blood cell counts of less than 3500/mm³ or an absolute neutrophil count (ANC) <1500/mm³ should lead to dose reductions, because lower counts are associated with a markedly increased risk of opportunistic infection. (By contrast, isolated lymphopenia, an anticipated effect although not a goal of therapy, does not indicate a need for altering the CYC dose.)

Marked lymphopenia is common during CYC therapy and is not a major cause for concern, as long as patients are also receiving routine P. jirovecii prophylaxis. However, the total white blood cell count should be maintained above 3500/mm³ and the dose reduced or held if leukopenia occurs. The goal of treatment is clinical improvement, which usually occurs without needing to induce leukopenia.

●Renal function – Serum creatinine, urea nitrogen, and electrolytes should also be measured every two to four weeks. Patients' underlying disease or other medications (eg, nonsteroidal antiinflammatory drugs [NSAIDs]) may affect renal function adversely. Declines in renal function may necessitate adjustment of the CYC dose. (See 'Drug dose for oral CYC' above.)

●Liver function tests – We typically obtain serum aminotransaminases every month while patients are on CYC given the risk of hepatotoxicity, albeit low. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Miscellaneous'.)

●Urinalysis – CYC-treated patients should have urinalyses every month while on CYC, and at least annually after its discontinuation. The presence of blood on dipstick should prompt a microscopic examination of the urine sediment. Hematuria may signal drug-induced cystitis, premalignant changes in the bladder epithelium, the development of frank bladder cancer, or the occurrence (or recurrence) of glomerulonephritis. In the absence of clinical findings that strongly suggest glomerulonephritis (eg, significant new/increasing proteinuria, red blood cell casts, and a rising serum creatinine), cystoscopy should be performed promptly as the next test in the evaluation of hematuria. Failure to promptly evaluate significant hematuria can lead to future uncertainty as to whether hemorrhagic cystitis, a contraindication to further CYC administration, has occurred. (See "Clinical presentation, diagnosis, and staging of bladder cancer" and "Etiology and evaluation of hematuria in adults".)

Interpreting the presence of hematuria is clearly more difficult in patients with systemic lupus or vasculitis who have hematuria at baseline because of renal involvement. In this setting, a clue to the development of bladder toxicity is an increase in hematuria in the absence of cellular casts, dysmorphic cells on urinalysis, or other signs of active systemic disease and without laboratory evidence of worsening renal function.

●Urine cytology – We obtain annual urine cytology indefinitely for patients who have received daily CYC. However, there is inadequate evidence to determine the optimal approach to screening for bladder toxicity after CYC use. (See "Screening for bladder cancer".)

CYCLOPHOSPHAMIDE IN THE INTENSIVE CARE UNIT — Circumstances may arise where cyclophosphamide (CYC) is administered to a patient on a mechanical ventilator or with a decreased level of consciousness. Either daily or pulse dosing regimens can be given in this setting (either by feeding tube for the former or intravenously for either).

The major concern is bladder protection. Catheter drainage should adequately protect the bladder if the urine output is greater than 100 mL/hour. Continuous bladder irrigation through a three-way catheter is necessary in patients with a lower urine output.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY AND RECOMMENDATIONS

●General principles – Cyclophosphamide (CYC), an alkylating agent, is one of the most potent immunosuppressive therapies available. Although very effective, CYC has the potential for devastating toxicity both in the short and long term. Two major aims in the use of CYC are prompt control of the underlying disease and discontinuation of the medication as soon as possible, replacing it with a less toxic alternative to minimize the short- and long-term morbidity that often results from CYC itself. (See 'Introduction' above.)

●Pharmacology – The metabolism and excretion of CYC are important issues related to its toxicity. The active metabolites are highly protein-bound and distributed to all tissues. Both active and inactive metabolites are primarily excreted unchanged in the urine, with elimination complete by 48 hours, with the potential for bladder toxicity leading to cancer. (See 'Pharmacology' above.)

●Relative contraindications – Relative contraindications to the use of CYC include active infection, neutropenia, pregnancy, lactation, and bladder cancer, or a history of prior CYC-induced cystitis. (See 'Contraindications' above.)

●Pretreatment evaluation – Prior to treatment with CYC, we routinely address the following (see 'Pretreatment evaluation' above):

•Interaction of CYC with other drugs, including those that alter the activity of hepatic enzymes, allopurinol, succinylcholine, and anticholinergic agents (see 'Drug interactions' above)

•Counseling on infertility risk and fertility preservation, and the importance of contraception (see 'Infertility risk' above and 'Contraception' above)

•Baseline laboratory testing including complete blood count with differential, serum creatinine levels, urinalysis, liver function tests, hepatitis B and C serologies (see 'Laboratory and clinical testing' above)

•Screening for cervical cancer and human papilloma virus (HPV) infection in females (see 'Laboratory and clinical testing' above)

•Screening for latent tuberculosis with tuberculin skin test (TST) or interferon-gamma release assays (IGRAs) (see 'Laboratory and clinical testing' above)

•Prophylaxis for Pneumocystis jirovecii (carinii) pneumonia infection (see 'Prophylaxis for Pneumocystis jirovecii pneumonia infection' above)

•Prevention of drug-induced cystitis with adequate hydration and Mesna (see 'Prevention of drug-induced cystitis' above)

•Appropriate immunizations prior to treatment (see 'Immunization requirements' above)

●Intermittent CYC administration – Intermittent CYC, usually administered intravenously every two or four weeks, is the most commonly used form of CYC in the treatment of systemic rheumatic diseases. One of the principal reasons for using intermittent CYC is concern about the long-term complications of daily oral therapy. Intravenous fluids, antiemetics, and Mesna may be used to prevent toxicities commonly associated with CYC. Selection of the initial dose of CYC for intravenous infusion should be adjusted for renal failure. Subsequent intravenous doses are further adjusted based upon the patient's response to therapy and the nadir of the white blood cell count. (See 'Intermittent (pulse) cyclophosphamide' above.)

●Oral CYC administration – Daily oral CYC remains an important treatment for life-threatening manifestations of systemic rheumatic diseases, but it has been largely replaced by the use of intermittent CYC. The daily dose should be modified in patients with diminished or improving renal function or on hemodialysis, with resistant disease, and in the setting of obesity. Regular and frequent laboratory evaluations are required to screen for bone marrow toxicity, monitor renal function, and avoid major drug-induced bladder complications. (See 'Daily oral cyclophosphamide' above.)

●CYC in the intensive care unit – Either daily or pulse dosing regimens can be used for patients on a mechanical ventilator or with a decreased level of consciousness to whom CYC is administered in the intensive care setting. Particular attention should be given to measures for bladder protection. (See 'Cyclophosphamide in the intensive care unit' above.)