Cyclophosphamide 500 mg powder for solution for injection or infusion - Summary of Product Characteristics (SmPC) (2023)

Cyclophosphamide 500 mg powder for solution for injection or infusion

Each vial of Cyclophosphamide 500 mg powder for solution for injection or infusion contains 534.5 mg cyclophosphamide monohydrate, equivalent to 500 mg cyclophosphamide.

Concentration after reconstitution: 20 mg cyclophosphamide (anhydrous)/ml solution (for reconstitution volumes see 6.6.)

For the full list of excipients see section 6.1.

Powder for solution for injection and infusion

white crystalline powder

Depending on the indication, cyclophosphamide can be used alone or in combination with other chemotherapeutic agents. Cyclophosphamide is indicated for the treatment of:

• Chronic Lymphocytic Leukemia (CLL)

• Acute Lymphocytic Leukemia (ALL)

• As conditioning for bone marrow transplantation, in the treatment of acute lymphoblastic leukemia, chronic myeloid leukemia and acute myeloid leukemia, in combination with total body irradiation or busulfan.

• Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma

• Metastatic ovarian and breast cancer

• Adjuvant treatment of breast cancer

• Sarcoma de Ewing

• Small cell lung cancer

• Advanced or metastatic neuroblastoma,

• Life-threatening autoimmune diseases: severe progressive forms of lupus nephritis and Wegener's granulomatosis.

Cyclophosphamide should only be used by physicians experienced in the use of cancer chemotherapy. Cyclophosphamide should only be administered where facilities are available for regular monitoring of clinical, biochemical and haematological parameters before, during and after administration and under the direction of a specialized oncology service.

dosage

The dosage must be adjusted individually. Dosages and duration of treatment or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the general state of health and the organ function of the patient as well as the results of the laboratory control (especially the control of the blood cells).

In combination with other cytostatics of similar toxicity, a dose reduction or extension of therapy-free intervals may be necessary.

The use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or to facilitate administration of the intended dose.

Adequate amounts of fluid should be ingested or infused before, during and immediately after administration to promote diuresis and reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning. See Section 4.4.

The decision on the use of cyclophosphamide is the responsibility of the physician according to the company's treatment guidelines.

The following dosages can be considered as general guidelines:

Hematological and solid tumors

for. For daily treatment:

3 6 mg/kg body weight (= 120 240 mg/m2 body surface area), injected intravenously

B. For intermittent treatment:

10 15 mg/kg body weight (= 400 600 mg/m2 body surface area), injected intravenously, 2 to 5 days apart without treatment.

C. For high-dose intermittent treatment:

20 - 40 mg/kg body weight (= 800 - 1600 mg/m2 body surface area) injected intravenously with treatment-free intervals of 21 to 28 days.

To prepare for a bone marrow transplant

Injected intravenously for 2 days 60 mg/kg or 4 days 50 mg/kg body weight.

If a busulfan-cyclophosphamide (Bu/Cy) regimen is used, the first cyclophosphamide dose should be administered at least 24 hours after the last busulfan dose (see sections 4.4 and 4.5).

autoimmune diseases

500-1000 mg/m2 body surface per month.

Patients with liver failure

Severe hepatic failure may be associated with reduced cyclophosphamide activation. This may alter the efficacy of cyclophosphamide treatment and should be considered when selecting the dose and interpreting the response to the chosen dose. (See section 4.4).

The dose should be reduced in patients with severe hepatic impairment. A dose reduction of 25% is recommended in patients with serum bilirubin concentrations of 3.1-5 mg/100 ml (= 0.053-0.086 mmol/l).

patients with renal failure

In patients with renal impairment, especially in patients with severe renal impairment, reduced renal excretion can lead to increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be considered when determining the dose in such patients. (See section 4.4). If the glomerular filtration rate is less than 10 ml/minute, a 50% dose reduction is recommended.

Cyclophosphamide and its metabolites are dialyzable, although there may be differences in clearance depending on the dialysis system used. In patients requiring dialysis, the use of a constant interval between administration of cyclophosphamide and dialysis should be considered. See Section 4.4.

Geezer

In elderly patients, monitoring for toxicity and the need for dose adjustment should reflect the greater frequency of impaired hepatic, renal, cardiac or other organ function and comorbid conditions or other drug therapy in this patient group.

pediatric population

Cyclophosphamide has been given to children. The safety profile of cyclophosphamide in pediatric patients is similar to that in adults.

Dose modification for myelosuppression

White blood cell and platelet counts should be performed regularly during treatment with cyclophosphamide. It is recommended that the dose may be adjusted if signs of myelosuppression appear.

Please see the table below. The urine sediment should also be checked regularly for the presence of erythrocytes.

In combination therapy it may be necessary to consider further dose reductions.

method of administration

Cyclophosphamide is inert until activated by liver enzymes. However, as with all cytotoxic agents, it is recommended that reconstitution be performed by trained personnel in a dedicated area.

Precautions to be taken before handling or administering the product

Persons handling the preparation must wear protective gloves..Care must be taken to ensure that the material does not splash into the eyes. The material must not be handled by pregnant or breastfeeding women.

The choice of solvent for the reconstitution of cyclophosphamide containing cyclophosphamide depends on the route of administration to be used.

Infusion:

If the solution is to be used for intravenous infusion, cyclophosphamide (which contains cyclophosphamide) is reconstituted by adding sterile water for injections or sterile sodium chloride 0.9% solution.

Reconstituted cyclophosphamide should be further diluted in 5% dextrose or 0.9% sodium chloride prior to infusion.

Direct injection:

If the solution is used for direct injection, cyclophosphamide (which contains cyclophosphamide) is reconstituted by the addition of sterile sodium chloride 0.9% solution.

Note that only cyclophosphamide reconstituted in sterile 0.9% sodium chloride solution is suitable for bolus injection.

Cyclophosphamide reconstituted in water (which contains cyclophosphamide) is hypotonic and should not be injected directly.

For detailed instructions on reconstitution see section 6.6.

intravenous use

Intravenous administration should preferably be done as an infusion.

To reduce the likelihood of side effects that appear to be frequency dependent (eg, facial swelling, headache, nasal congestion, burning scalp), cyclophosphamide should be injected or infused very slowly. The duration of the infusion (ranging from 30 minutes to 2 hours) should be appropriate for the volume and type of vehicle being infused.

Before intravenous administration, the substance must be completely dissolved.

Pharmaceutical products for intravenous use should be inspected visually for particulate matter and discoloration prior to administration, where the solution and packaging permit.

Cyclophosphamide is contraindicated in patients with:

• Hypersensitivity to cyclophosphamide or any of its metabolites

• acute infections

• Bone marrow aplasia or bone marrow depression prior to treatment

• Urinary tract infection

• Acute urothelial toxicity from cytotoxic chemotherapy or radiotherapy

• Urinary flow

• Disability

• Lactation (see Section 4.6)

Cyclophosphamide should not be used to treat non-malignant diseases, except for immunosuppression in life-threatening situations.

HINTS

Anaphylactic reactions, cross-sensitivity to other alkylating agents

Anaphylactic reactions, including fatal ones, have been reported with cyclophosphamide. Possible cross sensitivity with other alkylating agents has been reported.

Treatment with cyclophosphamide can cause myelosuppression (anaemia, leukopenia, neutropenia, and thrombocytopenia) and significant suppression of the immune response, which can lead to serious, sometimes fatal, infections, sepsis, and septic shock. Infections that have been reported with cyclophosphamide include pneumonia and other bacterial, fungal, viral, protozoal, and parasitic infections.

Latent infections can be reactivated. Reactivation of various bacterial, fungal, viral, protozoal and parasitic infections has been reported.

Infections occurring during treatment with cyclophosphamide, including febrile neutropenia, should be treated appropriately. In certain cases of neutropenia, antimicrobial prophylaxis may be indicated (at the discretion of the treating physician). Antibiotics and/or antifungals should be given for neutropenic fever. Cyclophosphamide should be used with caution (or not at all) in patientsfunctional impairmentvonbone marrowand patients with severe immunosuppression.

Close haematological monitoring of all patients is required during treatment. Haematological parameters should be checked prior to each administration and periodically during treatment. More frequent monitoring may be necessary if the white blood cell count falls below 3000 cells/microliter (cells/mm³). Dose adjustment is recommended due to myelosuppression (see section 4.2).

Unless absolutely necessary, cyclophosphamide should be given to patients with a white blood cell count below 2500 cells/microliter (cells/mm³) and/or platelet count less than 50,000 cells/microliter (cells/mm³).

In general, the fall in peripheral blood cell and platelet counts and the time required for recovery may increase with increasing doses of cyclophosphamide.

The nadirs in white blood cell and platelet count decreases are generally reached at weeks 1 and 2 of treatment. The bone marrow recovers relatively quickly, and peripheral blood cell counts usually return to normal after about 20 days.

In patients who have or develop a serious infection, treatment with cyclophosphamide may not be indicated or should be discontinued or the dose reduced.

Severe myelosuppression should be expected, particularly in patients previously treated and/or receiving concomitant chemotherapy and/or radiotherapy.

Urinary tract and kidney toxicity

Cases of haemorrhagic cystitis, pyelitis, ureteritis and haematuria have been reported with cyclophosphamide treatment. Bladder ulceration/necrosis, fibrosis/contracture, and secondary cancer may develop. Urotoxicity may necessitate discontinuation of treatment. Fatal cases of urotoxicity have been reported.

Urotoxicity can occur with short-term and long-term use of cyclophosphamide. Haemorrhagic cystitis has been reported after single doses of cyclophosphamide. Cystectomy may be necessary because of fibrosis, hemorrhage, or secondary malignancy. Prior or concomitant treatment with radiation or busulfan may increase the risk of cyclophosphamide-induced haemorrhagic cystitis. Cystitis is usually nonbacterial at first. Secondary bacterial colonization can occur.

Urinary tract obstruction must be ruled out or corrected before starting treatment. See Section 4.3. The urine sediment should be checked regularly for red blood cells and other signs of urotoxicity/nephrotoxicity. Appropriate treatment with Mesna and/or intensive fluid intake to promote diuresis can markedly reduce the frequency and severity of bladder toxicity. It is important to ensure that patients empty their bladders on a regular basis. Hematuria usually resolves within days of stopping treatment with cyclophosphamide, but may persist. Severe hemorrhagic cystitis usually requires discontinuation of cyclophosphamide treatment.

Cyclophosphamide has also been associated with nephrotoxicity, including renal tubular necrosis.

Hyponatraemia associated with increased total body water, acute water intoxication and a SIADH-like syndrome (syndrome of inappropriate ADH secretion) have been reported in association with the administration of cyclophosphamide. Fatal consequences have been reported.

Myocarditis and myopericarditis, which may be accompanied by extensive pericardial effusion and cardiac tamponade, and have resulted in severe, sometimes fatal, congestive heart failure have been reported with cyclophosphamide treatment. Histopathological examination showed mainly hemorrhagic myocarditis. Hemopericardium secondary to hemorrhagic myocarditis and myocardial necrosis has been reported. Acute cardiac toxicity has been reported with single doses as low as 20 mg/kg cyclophosphamide.

Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with cyclophosphamide in patients with and without other signs of cardiotoxicity.

The risk of cyclophosphamide cardiotoxicity resulting from treatment with cyclophosphamide may e.g. B. after high doses of cyclophosphamide, in elderly patients and in patients with prior irradiation of the cardiac region and / or prior or concomitant treatment with other cardiotoxic agents. See Section 4.5.

Particular caution is required in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.

lung toxicity

Cases of pneumonitis and pulmonary fibrosis have been reported during and after treatment with cyclophosphamide. Pulmonary veno-occlusive disease and other forms of lung toxicity have also been reported. Pulmonary toxicity resulting in respiratory failure has been reported. Although the incidence of cyclophosphamide-associated pulmonary toxicity is low, the prognosis for affected patients is poor. Late-onset pneumonitis (more than 6 months after initiation of cyclophosphamide treatment) appears to be associated with a particularly high mortality rate. Pneumonia can develop years after treatment with cyclophosphamide. Acute pulmonary toxicity has been reported after a single dose of cyclophosphamide.

Secondary neoplasms

As with any cytotoxic therapy, treatment with cyclophosphamide carries the risk of secondary tumors and their precursors as sequelae.

The risk of urinary tract cancer is increased, as is the risk of myelodysplastic diseases, some of which progress to acute leukemia. Other malignancies that have been reported following use of cyclophosphamide or regimens containing cyclophosphamide include lymphoma, thyroid cancer and sarcoma.

In some cases, the second malignancy has developed several years after stopping cyclophosphamide treatment. Malignancy has also been reported after in utero exposure.

The risk of bladder cancer can be significantly reduced by prophylaxis against hemorrhagic cystitis.

Veno-occlusive liver disease (VOLD) has been reported in patients receiving cyclophosphamide, mainly in patients receiving a debulking regimen in preparation for bone marrow transplantation in combination with total body irradiation, busulfan or other agents (see section 4.5). After cytoreductive therapy, the clinical syndrome usually develops 1 to 2 weeks after transplantation and is characterized by sudden weight gain, painful hepatomegaly, ascites, and hyperbilirubinemia/jaundice. However, VOLD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive cyclophosphamide.

Complications of VOLD can include hepatorenal syndrome and multiple organ failure. One fatal outcome of VOLD associated with cyclophosphamide has been reported. Risk factors that predispose a patient to developing VOLD include pre-existing liver dysfunction, prior radiation therapy to the abdomen, and poor performance.

It has been reported that the incidence of VOLD is reduced when a time interval of at least 24 hours is observed between the last busulfan dose and the first cyclophosphamide dose (see sections 4.2 and 4.5).

genotoxicity

Cyclophosphamide is genotoxic and mutagenic both in body cells and in male and female germ cells. Therefore, women should not become pregnant and men should not have children while taking cyclophosphamide.

Women must not become pregnant during treatment and for a period of 12 months after stopping therapy.

Men should not father a child during treatment and for a period of 6 months after stopping therapy.

Animal data indicate that exposure of oocytes during follicular development can result in reduced implantation rates and viable pregnancies, as well as an increased risk of malformations. This effect should be taken into account in case of anticipated fertilization or pregnancy after stopping treatment with cyclophosphamide. The exact duration of follicle development in humans is not known, but it can be longer than 12 months. Sexually active men and women should use effective contraception during this time (see section 4.6.).

fertility

Cyclophosphamide disrupts oogenesis and spermatogenesis. It can cause infertility in both sexes. Men treated with cyclophosphamide should be informed about sperm preservation prior to treatment (see section 4.6).

Impaired wound healing

Cyclophosphamide can interfere with normal wound healing.

PRECAUTIONS

alopecia

Alopecia has been reported and may occur more frequently with increasing dose. Alopecia can progress to baldness. The hair can be expected to grow back after treatment with the drug, or even during continued treatment with the drug, although it may be a different texture or color.

nausea and vomiting

Administration of cyclophosphamide can cause nausea and vomiting. Current guidelines on the use of antiemetics to prevent and relieve nausea and vomiting should be considered.

Alcohol consumption can increase cyclophosphamide-induced vomiting and nausea.

Stomatitis

Administration of cyclophosphamide can cause stomatitis (oral mucositis). Current guidelines on measures to prevent and improve stomatitis should be considered.

The cytostatic effect of cyclophosphamide occurs after its activation, which takes place mainly in the liver. Therefore, the risk of tissue damage from accidental paravenous administration is low.

In the event of accidental paravenous administration of cyclophosphamide, the infusion should be stopped immediately, the extravascular cyclophosphamide solution should be aspirated with the cannula attached and other measures instituted as necessary. The area should then be flushed with saline solution and the arm or leg rested.

Use in patients with impaired renal function

In patients with renal impairment, especially in patients with severe renal impairment, reduced renal excretion can lead to increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be considered when determining the dose in such patients. See Section 4.2.

Use in patients with impaired liver function

Severe hepatic impairment may be associated with a decrease in the effect of cyclophosphamide. This may affect the efficacy of treatment with cyclophosphamide and should be considered when selecting the dose and interpreting the response to the chosen dose. See Section 4.2. Due to the porphyrogenic effect of cyclophosphamide, patients with acute porphyria should be treated with caution.

Use in adrenalectomized patients

Patients with adrenal insufficiency may require an increased replacement dose of corticosteroids when exposed to stress from cytostatic toxicity, including cyclophosphamide.

Use in patients with diabetes mellitus

Caution is also required in patients with diabetes mellitus, as cyclophosphamide can interact with insulin and other antidiabetics (see also section 4.5).

Use in patients who have recently undergone surgery

In general, cytotoxic drugs (including cyclophosphamide) should not be given to patients who have had surgery less than 10 days ago.

Cyclophosphamide is inactive but is metabolised in the liver to two active metabolites, mainly by CYP2A6, 2B6, 2C9, 2C19 and 3A4.

The planned simultaneous or sequential administration of other substances or treatments with cyclophosphamide that may increase the likelihood or severity of toxic effects (through pharmacodynamic or pharmacokinetic interactions) requires careful individual assessment of the expected benefit and risk.

Patients receiving these combinations should be closely monitored for signs of toxicity to allow for timely intervention. Patients treated with cyclophosphamide and agents that decrease its activation should be monitored for possible reduced therapeutic efficacy and the need for dose adjustment.

Interactions affecting the pharmacokinetics of cyclophosphamide and its metabolites

• Decreased activation of cyclophosphamide may reduce the effectiveness of cyclophosphamide treatment. Substances that delay activation of cyclophosphamide include:

- Aprepitant

- Bupropion

- Busulfan: Decreased cyclophosphamide clearance and increased half-life have been reported in patients receiving high-dose cyclophosphamide less than 24 hours after high-dose busulfan. An increased incidence of hepatic veno-occlusive disease and mucositis has been reported with concomitant use (see sections 4.2 and 4.4).

- Ciprofloxacin: When given before treatment with cyclophosphamide (for conditioning before bone marrow transplantation), ciprofloxacin can cause regression of the underlying disease.

- Cloranfenicol

- Azole antifungals (fluconazole, itraconazole): Azole antifungals are known to inhibit cytochrome P450 enzymes. Increased levels of toxic degradation products have been reported with cyclophosphamide in combination with itraconazole.

- CYP2B6 and CYP3A4 inhibitors (nevirapine, ritonavir): Concomitant use may reduce the effectiveness of cyclophosphamide

- Prasugrel

- Sulfonamide, z.B. Sulfadiazin, Sulfamethoxazol und Sulfapyridin

- Thiotepa: Potent inhibition of cyclophosphamide bioactivation by thiotepa has been reported in high-dose chemotherapy regimens when thiotepa was administered 1 hour before cyclophosphamide.

- Ondansetron: There have been reports of a pharmacokinetic interaction between ondansetron and cyclophosphamide at high doses, resulting in decreased AUC of cyclophosphamide.

- Grapefruit (fruit or juice), Rifampicin, St. Johnsworth: Concomitant use with CYP3A4 inhibitors or inducers may decrease the efficacy or increase the toxicity of cyclophosphamide.

• An increased concentration of cytotoxic metabolites can occur with:

- Allopurinol: Increased bone marrow suppression has been reported.

- Azathioprine: increased risk of liver toxicity (hepatic necrosis)

- Chloralhydrat

- Cimetidine

- Disulfiram

- Glycerinaldehyd

- Protease inhibitors: Concomitant use of protease inhibitors can increase the concentration of cytotoxic metabolites. In patients receiving cyclophosphamide, doxorubicin and etoposide (CDE), use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia than use of an NNRTI-based regimen. Increased occurrence of mucositis in combination therapy with cyclophosphamide (CDE) and saquinavir

- Inducers of human hepatic and extrahepatic microsomal enzymes (e.g. cytochrome P450 enzymes): The potential to induce hepatic and extrahepatic microsomal enzymes should be considered in case of prior or concomitant treatment with substances known to cause their Activity increase enzymes such as rifampicin. , phenobarbital, carbamazepine, phenytoin, St. John's wort, benzodiazepines and corticosteroids.

- Dabrafenibe

The combined or sequential use of cyclophosphamide and other agents with similar toxicity can cause combined (increased) toxic effects.

• Increased haematotoxicity and/or immunosuppression can result from a combined effect of cyclophosphamide and e.g. B.

- ACE inhibitors: ACE inhibitors can cause leukopenia.

- Natalizumab

- Paclitaxel: Increased haematotoxicity has been reported when cyclophosphamide was administered after a paclitaxel infusion.

- Thiazide diuretics (e.g. hydrochlorothiazide): Increased bone marrow suppression has been reported.

- Zidovudine

- Clozapine

• Increased cardiotoxicity can result from a combined effect of cyclophosphamide and e.g. B.

- Anthrazykline

- Mitomicin

-citabina

- Pentostatina

- Radiation therapy to the region of the heart or radiation to the whole body in combination with high doses of cyclophosphamide

- Trastuzumabe

• Increased pulmonary toxicity can be caused by a combined effect of cyclophosphamide and e.g. B.

- Amiodarone

- G-CSF, GM-CSF (granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor): reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy regimens including cyclophosphamide and G- CSF or GMCSF.

• Increased nephrotoxicity can be caused by a combined effect of cyclophosphamide and e.g. B.

- Amphotericin B

- Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin.

Other Interactions

• Alcohol

Reduced antitumor activity was observed in tumor-bearing animals during ethanol (alcohol) consumption and concomitant oral medication with low-dose cyclophosphamide. Alcohol may increase cyclophosphamide-induced vomiting and nausea in some patients.

• Etanercept

In patients with Wegener's granulomatosis, the addition of etanercept to standard therapy, including cyclophosphamide, has been associated with an increased incidence of solid non-cutaneous malignancies.

• Metronidazole

Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. The causal relationship is unclear.

In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.

• Tamoxifen

Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Interactions affecting the pharmacokinetics and/or effects of other drugs

• Bupropion

The metabolism of cyclophosphamide by CYP2B6 can inhibit the metabolism of bupropion.

• Cumarine

Increases and decreases in the effects of warfarin have been reported in patients receiving warfarin and cyclophosphamide.

• Cyclosporin

Lower serum cyclosporine concentrations were observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving cyclosporine alone. This interaction can lead to an increased incidence of Graft-versus-Host-Disease (GVHD).

• Depolarizing Muscular Relaxants

Treatment with cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity. With concomitant use of depolarizing muscle relaxants (e.g. succinylcholine, suxamethonium), prolonged apnea may occur as a result of reduced levels of pseudocholinesterase. If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be notified.

• Digoxin, β-Acetyldigoxin

Impaired absorption of digoxin and β-acetyldigoxin tablets has been reported with concomitant cytotoxic therapy.

• Vaccinations

The immunosuppressive effects of cyclophosphamide are expected to reduce the response to vaccination. Use of live vaccines can cause vaccine-induced infection.

• Verapamil

Impaired intestinal absorption of orally administered verapamil has been reported.

• Sulfonylharnstoff-Derivate

With the simultaneous use of cyclophosphamide and sulfonylurea derivatives, the blood sugar level can decrease.

women of childbearing age

Girls treated with cyclophosphamide during the prepubertal period usually develop normal secondary sexual characteristics and menstruate regularly.

Girls treated with cyclophosphamide during the prepubertal period later became pregnant.

Girls treated with cyclophosphamide whose ovarian function has been preserved after the end of treatment are at an increased risk of developing premature menopause (stopping menstruation before the age of 40).

Contraception in men and women.

Women must not become pregnant during treatment and for a period of 12 months after stopping therapy.

Men should not father a child during treatment and for a period of 6 months after stopping therapy.

Sexually active men and women should use an effective method of contraception during these times.

the pregnancy

There are very limited data from the use of cyclophosphamide in pregnant women. There have been reports of severe multiple congenital aberrations after use during the first trimester.

Animal studies have shown teratogenicity and other reproductive toxicity (see section 5.3).

Based on data from human case reports, animal studies and the mechanism of action of cyclophosphamide, its use during pregnancy, especially during the first trimester, is not recommended.

In each individual case, the potential benefit of the treatment must be weighed against the potential risk to the foetus.

breastfeeding

Cyclophosphamide is excreted in breast milk and can cause neutropenia, thrombocytopenia, low hemoglobin, and diarrhea in infants. Cyclophosphamide is contraindicated during lactation (see section 4.3).

fertility

Cyclophosphamide disrupts oogenesis and spermatogenesis. It can cause infertility in both sexes. Cyclophosphamide can cause transient or permanent amenorrhea in women and oligospermia or azoospermia in children treated with cyclophosphamide during prepuberty. Men treated with cyclophosphamide may develop oligospermia or azoospermia. Before treating men with cyclophosphamide, they should be informed of the possibility of saving and storing viable sperm collected prior to treatment.

Side effects (including nausea, vomiting, dizziness, blurred vision, visual disturbances) that may affect the ability to drive or use machines may occur in patients treated with cyclophosphamide. The decision to drive or use machines must be made on an individual basis.

The frequencies of adverse reactions presented in the table below are based on clinical trials and post-marketing experience and are defined using the following convention: very common (

1/10), common (

1/100 to < 1/10), occasionally (

1/1000 to <1/100), rare (

1/10,000 to <1/1,000), very rare (<1/10,000) unknown.

1 Increased risk and severity of pneumonia (including fatal outcomes), other bacterial, fungal, viral, protozoal and parasitic infections; reactivation of latent infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leukoencephalopathy (including fatal consequences),Pneumocystisjiroveci, herpes infection,estrongiloides, sepsis and septic shock (including fatal consequences).

2 including fatalities

3 including acute myeloid leukemia, acute promyelocytic leukemia

4 Manifest as bone marrow failure, pancytopenia, neutropenia, agranulocytosis, granulocytopenia, thrombocytopenia (complicated by bleeding), leukopenia, anemia

5 manifests as myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paraesthesia, tremor, dysgeusia, hypogeusia, parosmia.

6 Manifested as headaches, altered mental functioning, seizures, and abnormal vision ranging from blurred vision to vision loss

7 Seen associated with an allergic reaction

8 Including fatal consequences

9 Although the incidence of cyclophosphamide-associated pulmonary toxicity is low, the prognosis for affected patients is poor.

10 Hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, jaundice, increased blood bilirubin, increased hepatic enzymes (ASAT, ALAT, ALP, gamma-GT)

May 11 advances to baldness

12 Of palms and heels

13 stubborn

Monitoring:

Certain complications such as thromboembolism, disseminated intravascular coagulation, and hemolytic-uremic syndrome can occur as a consequence of the underlying diseases, but the frequency of these complications may be increased by cyclophosphamide chemotherapy.

Notification of Suspected Side Effects

It is important to report suspected adverse drug reactions after approval. Allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

Serious consequences of overdose include manifestations of dose-dependent toxicity such as myelosuppression, urotoxicity, cardiotoxicity (including heart failure), occlusive venous liver disease and stomatitis. See Section 4.4.

Patients who receive an overdose should be carefully monitored for the development of toxicities, particularly haematotoxicity.

There is no specific antidote for cyclophosphamide overdose.

Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating suicidal or accidental overdose or poisoning.

Overdose should be managed with supportive measures, including appropriate state-of-the-art treatment for any co-infection, myelosuppression, or other toxicity, should it occur.

Mesna cystitis prophylaxis may help prevent or reduce the urotoxic effects of cyclophosphamide overdose.

Pharmacotherapeutic group: Antineoplastic and immunomodulatory agents; antineoplastic agents. Agent rental. nitrogen mustard analogues

ATC-Code: L01AA01.

Cyclophosphamide has a cytostatic effect on many tumor types.

Cyclophosphamide is likely involved in the S or G2 phase of the cell cycle.

It remains to be seen whether the cytostatic effect is entirely dependent on DNA alkylation or whether other mechanisms such as inhibition of chromatin transformation processes or inhibition of DNA polymerases play a role. The acrolein metabolite has no antineoplastic activity but is responsible for the adverse urotoxic effect.

Cyclophosphamide's immunosuppressive effect is due to cyclophosphamide's inhibitory effects on B cells, CD4+ T cells and, to a lesser extent, CD8+ T cells. Furthermore, cyclophosphamide is said to have an inhibitory effect on the suppressor-regulatory IgG2 antibody class.

Cross-resistance, especially with structurally related cytostatics, e.g. Ifosfamide and other alkylating agents cannot be excluded.

Cyclophosphamide is administered as an inactive prodrug that is activated in the liver.

Absorption

Cyclophosphamide is rapidly and almost completely absorbed from the parenteral sites.

distribution

Less than 20% of cyclophosphamide is bound to plasma proteins. Protein binding of cyclophosphamide metabolites is greater but less than 70%. The extent to which the active metabolites bind to the protein is unknown.

Cyclophosphamide is found in cerebrospinal fluid and breast milk. Cyclophosphamide and its metabolites can cross the placenta.

metabolism

Cyclophosphamide is activated in the liver to the active metabolites 4-hydroxy-cyclophosphamide and aldophosphamide (tautomeric form of 4-hydroxy-cyclophosphamide) by phase I metabolism by cytochrome P450 (CYP) enzymes. Various CYP isoenzymes contribute to cyclophosphamide bioactivation, including CYP2A6, 2B6, 2C9, 2C19 and 3A4, 2B6, where it has the highest 4-hydroxylase activity. Detoxification occurs mainly through glutathione S-transferases (GSTA1, GSTP1) and alcohol dehydrogenase (ALDH1, ALDH3). Plasma concentrations of the active metabolites peak two to four hours after administration of cyclophosphamide, after which there is a rapid decrease in plasma concentrations.

elimination

The plasma half-life of cyclophosphamide is approximately 4 to 8 hours in adults and children. The plasma half-life of the active metabolites is unknown.

After high-dose intravenous administration in the context of allogeneic bone marrow transplantation, the plasma concentration of pure cyclophosphamide follows first-order linear kinetics. Compared to conventional cyclophosphamide therapy, there is an increase in inactive metabolites, indicating saturation of the activating enzyme systems but not of the metabolic steps leading to inactive metabolites. In the course of therapy with high-dose cyclophosphamide for several days, the areas under the plasma concentration-time curve of the parent substance decrease, probably due to autoinduction of microsomal metabolic activity.

Cyclophosphamide and its metabolites are primarily eliminated via the kidneys.

acute toxicity

The acute toxicity of cyclophosphamide is relatively low. This has been shown in studies with mice, guinea pigs, rabbits and dogs.

chronic toxicity

Chronic administration of toxic doses caused liver damage, manifested as fatty degeneration with subsequent necrosis. The intestinal mucosa was not affected. The threshold for hepatotoxic effects was 100 mg/kg in rabbits and 10 mg/kg in dogs.

Mutagenicity and Carcinogenicity

The mutagenic effect of cyclophosphamide has been demonstrated in severalin-vitrojLive-Tests. Chromosomal aberrations have also been observed in humans after administration of cyclophosphamide. The carcinogenic effect of cyclophosphamide was demonstrated in animal experiments on rats and mice.

teratogenicity

Isteratogenic effectsCyclophosphamide has been detected in several animals (mice, rats, rabbits, rhesus monkeys and dogs). Cyclophosphamide can cause skeletal, tissue, and other deformities.

none

Not applicable

2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C for the reconstituted solution and the diluted solution.

From a microbiological point of view, the reconstituted and diluted solution should be used immediately unless reconstitution has taken place in controlled and validated aseptic conditions. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C.

Do not store above 25°C.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Cyclophosphamide 500 mg powder for solution for injection or infusion is available in the following pharmaceutical forms:

1, 5 or 10 50 ml clear and colorless type I glass vials containing 500 mg cyclophosphamide, closed with an uncoated bromobutyl stopper and protected with a flip-off seal with a red PP button

Not all pack sizes may be marketed.

Vials are packed with or without a protective plastic film (Onco-Safe). Onco-Safe does not come into contact with the medication and provides additional protection during transport, increasing the safety of medical and pharmaceutical staff.

For every 100 mg of cyclophosphamide, 5 ml of solvent should be added for reconstitution.

The choice of diluent for reconstitution of cyclophosphamide-containing cyclophosphamide depends on the route of administration to be used.

Direct injection:

If the solution is used for direct injection, cyclophosphamide (which contains cyclophosphamide) is reconstituted by the addition of sterile sodium chloride 0.9% solution.

Infusion:

If the solution is to be used for intravenous infusion, cyclophosphamide (which contains cyclophosphamide) is reconstituted by adding sterile water for injections or sterile sodium chloride 0.9% solution.

The following amounts of water for injections or sodium chloride 0.9% solution are added to vials of cyclophosphamide, powder for solution for injection or solution for infusion.

Frasco de 500 mg: 25 ml

Frasco de 1000 mg: 50 ml

Frasco de 2000 mg: 100 ml

When injecting the solvent into the vial, an unusually high pressure is created, which disappears as soon as the second sterile needle is inserted into the rubber stopper of the vial. The powder dissolves easily when the vial is shaken vigorously to obtain a clear solution. If the powder does not dissolve immediately, continue to shake the vial vigorously for a few minutes until the powder is completely dissolved. The solution should be administered as soon as possible after reconstitution.

After reconstitution, the solution is clear and colorless to light yellow. Please check the bottle before further use. Only clear solutions should be used.

Cyclophosphamide powder for injection or infusion reconstituted in water for injections has an osmolarity of 92 mOsm/kg.

Cyclophosphamide powder for injection or infusion reconstituted in 0.9% sodium chloride has an osmolarity of 353 mOsm/kg and a pH of 4.6

intravenous use

Intravenous administration should preferably be done as an infusion.

Infusion:

Reconstituted cyclophosphamide should be further diluted with dextrose 5% solution for injection or sodium chloride 0.9% solution prior to infusion.

Direct injection:

Note that only cyclophosphamide reconstituted in sterile 0.9% sodium chloride solution is suitable for bolus injection.

Cyclophosphamide reconstituted in water (which contains cyclophosphamide) is hypotonic and should not be injected directly.

When reconstituting and handling cyclophosphamide, the general rules and regulations for handling cytostatics must be observed. As far as possible, the reconstitution must be carried out in aSafety through laminar air flowCabinet. The person handling the product must wear a protective mask andGloves. In the event of a spill, the area should be thoroughly flushed with water. If cyclophosphamide powder for solution for injection or infusion is stored above the maximum temperature (e.g. during transport), cyclophosphamide can melt. Injection vials with melted cyclophosphamide can be recognized visually. Cyclophosphamide is a white powder. SUBWAYimproved cyclophosphamideIt is aof course theYellowish viscous liquid (usually found as droplets in affected vials). Injection vials with melted cyclophosphamide must no longer be used.

limited sandoz

Park view, Riverside-Weg

wachmoor park

Camberley, Surrey

GU15 3J

Great Britain

Date of first registration: August 18, 2014

First renewal date: 07/23/2019