Cyclophosphamide

Cyclophosphamide is a phosphoramide cytotoxic agent of the nitrogen mustard group. It is a prodrug that the liver must activate, which is why oral and intravenous administration are preferred. Its active metabolites damage DNA, and the SmPC describes the action as specific to the S phase of the cell cycle. It also suppresses the immune response markedly, which is the basis of its use in transplantation and autoimmune disease.

Mechanism of Action

• Activation: hepatic cytochrome P450 enzymes convert cyclophosphamide to 4-hydroxylated intermediates and then to the active metabolites phosphoramide mustard and acrolein (the SmPC also names aldophosphamide and nornitrogen mustard). DrugBank puts the activated share at about 75% of a dose. CYP2B6 has the highest 4-hydroxylase activity, and CYP2A6, 3A4, 3A5, 2C9, 2C18 and 2C19 also contribute.
• DNA alkylation: the active metabolites attach alkyl groups to nucleophilic atoms of the nucleic bases and form inter- and intra-strand cross-links in the DNA double helix. The strands can then no longer separate, so replication and transcription are blocked and the cell cannot divide. Base mispairing can also cause mutations.
• Self-induction: with repeated dosing, cyclophosphamide appears to induce its own metabolism, which raises clearance, increases formation of 4-hydroxy metabolites and shortens the half-life.
• Cross-resistance: cross-resistance cannot be excluded with similar cytostatics such as ifosfamide, or with other alkylating agents.

Pharmacokinetics

• Absorption: oral bioavailability is about 76%. After an oral dose, peak plasma concentrations occur at about 1 hour.
• Distribution: apparent volume of distribution 0.62 L/kg; the drug is widely distributed and crosses the blood–brain barrier. About 14% of cyclophosphamide is bound to plasma proteins, against about 60% for its active metabolites.
• Metabolism: in the liver, to metabolites with significant biological activity (see above).
• Elimination: mainly in urine as metabolites (85–90% of a dose). The elimination half-life is 4–7.5 hours for cyclophosphamide and 8.7 hours for aldophosphamide. Haemodialysis or peritoneal dialysis can remove 30–60% of a dose.
• Special populations: in renal impairment the half-life lengthens to about 10 hours for cyclophosphamide and 13 hours for aldophosphamide, and reduced excretion can raise levels of the drug and its metabolites. Severe hepatic impairment can reduce activation and so alter efficacy.

Cyclophosphamide is indicated within a combination chemotherapy regimen or as monotherapy in the following. The same list applies to the coated tablets and to the powder for injection or infusion.

• Lymphoma and myeloma: Hodgkin lymphoma, non-Hodgkin lymphomas and multiple myeloma.
• Leukaemia: chronic lymphocytic leukaemia, acute lymphocytic leukaemia, chronic myeloid leukaemia and acute lymphoblastic leukaemia.
• Solid tumours: Ewing sarcoma; advanced or metastatic neuroblastoma; metastatic breast and ovarian carcinoma; adjuvant treatment of breast carcinoma; small cell lung carcinoma.
• Transplantation: as an immunosuppressant in organ and bone marrow transplantation.
• Autoimmune and rheumatological disease: autoimmune diseases such as Wegener’s granulomatosis (granulomatosis with polyangiitis) and progressive severe forms of systemic lupus erythematosus (lupus nephritis).

The SmPC also states that cyclophosphamide must not be used for non-malignant diseases other than immunosuppression in life-threatening situations (see Contraindications).

• Hypersensitivity to cyclophosphamide, to any of its metabolites or to any excipient.
• Active infections.
• Severe bone marrow dysfunction, in particular in patients pre-treated with cytotoxic medicines or radiotherapy.
• Cystitis (bladder inflammation) and obstruction of the urinary tract.
• Acute urothelial toxicity from cytotoxic chemotherapy or radiotherapy.
• Pregnancy and breastfeeding.
• Non-malignant disease: the SmPC states that it should not be used to treat these, except for immunosuppression in life-threatening situations.

The frequencies below come from clinical trials and post-marketing experience, and many reactions are dose-dependent. Bone marrow suppression, immunosuppression, nausea and vomiting, hair loss and bladder irritation are the most typical; moderate to severe nausea and vomiting occur in roughly half of patients.

Very common (≥1/10): myelosuppression, leukopenia, neutropenia, immunosuppression, nausea, vomiting, alopecia, cystitis, microscopic haematuria, fever.

Common (≥1/100 to <1/10): febrile neutropenia, infections, haemorrhagic cystitis, macroscopic haematuria, impaired spermatogenesis, baldness, chills, asthenia, fatigue, malaise, mucositis.

Uncommon (≥1/1,000 to <1/100): thrombocytopenia, anaemia, pneumonia, sepsis, anorexia, cardiomyopathy, myocarditis, heart failure, tachycardia, peripheral neuropathy, polyneuropathy, neuralgia, hypersensitivity and anaphylactic or anaphylactoid reactions, ovulation disorders, reduced female sex hormone levels, amenorrhoea, raised lactate dehydrogenase and C-reactive protein, ECG changes, reduced left ventricular ejection fraction.

Rare (≥1/10,000 to <1/1,000): ventricular and supraventricular arrhythmias, convulsion, blurred vision, stomatitis, diarrhoea, constipation, abdominal pain, parotid gland inflammation, dehydration, rash, dermatitis, skin inflammation, haemorrhage, chest pain, impaired liver function, hepatitis, azoospermia, persistent oligospermia, and secondary cancers (acute myeloid leukaemia, acute promyelocytic leukaemia, myelodysplastic syndrome, bladder and urinary tract cancer, other secondary tumours).

Very rare (<1/10,000): disseminated intravascular coagulation, haemolytic uraemic syndrome; cardiac arrest, ventricular fibrillation, angina pectoris, myocardial infarction, pericarditis; visual impairment, conjunctivitis, eye oedema; deafness; acute respiratory distress syndrome, chronic interstitial pulmonary fibrosis, toxic pulmonary oedema, bronchospasm, dyspnoea, hypoxia, cough, pleural effusion; haemorrhagic enterocolitis, acute pancreatitis, ascites, mucosal ulceration, gastrointestinal haemorrhage, colitis, enteritis, typhlitis; bladder wall oedema, interstitial bladder inflammation with fibrosis and sclerosis, suburethral haemorrhage, renal impairment, renal failure, raised blood creatinine; Stevens-Johnson syndrome, toxic epidermal necrolysis, other severe skin reactions, discolouration of the palms, soles and nails, erythema in the irradiated area, toxic skin eruption; rhabdomyolysis, muscle cramps; hyponatraemia, fluid retention; septic shock; tumour lysis syndrome; thromboembolism, hypertension, hypotension; headache, pain, multi-organ failure; hepatic veno-occlusive disease, activation of hepatitis virus, hepatomegaly, jaundice; confusion; anaphylactic shock; dysgeusia, hypogeusia, dizziness, hepatic encephalopathy, paraesthesia; weight gain.

Not known: pancytopenia, agranulocytosis, granulocytopenia, lymphopenia, decreased haemoglobin; atrial fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion, myocardial haemorrhage, left ventricular failure, bradycardia, palpitations, QT prolongation; foetal death, foetal malformation, foetal growth retardation and toxicity; posterior reversible encephalopathy syndrome, myelopathy, dysaesthesia, hypoaesthesia, parosmia, encephalopathy; increased lacrimation; hearing impairment, tinnitus; pneumonitis, pulmonary veno-occlusive disease, bronchiolitis obliterans, organising pneumonia, allergic alveolitis; renal tubular necrosis and tubular disorder, toxic nephropathy, haemorrhagic ureteritis, ulcerative cystitis, bladder contracture, nephrogenic diabetes insipidus, atypical bladder epithelial cells, raised blood urea nitrogen; pruritus, erythema multiforme, palmar-plantar erythrodysaesthesia, urticaria, blisters, facial swelling, hyperhidrosis; scleroderma, muscle spasms, myalgia, arthralgia; water intoxication; raised or lowered blood glucose; progression of the underlying cancer, non-Hodgkin lymphoma, sarcoma, renal cell carcinoma, cancer of the renal pelvis or thyroid, carcinogenic effect in offspring; pulmonary embolism, venous thrombosis, vasculitis, peripheral ischaemia, flushing; pyrexia, oedema, influenza-like symptoms; premature labour; cholestatic and cytolytic hepatitis, cholestasis, hepatotoxicity with liver failure, raised bilirubin and liver enzymes; infertility, ovarian failure, oligomenorrhoea, testicular atrophy, decreased oestrogen, raised gonadotropins; abdominal discomfort.

The SmPC text adds that, depending on the dose, myelosuppression very frequently causes leukopenia, neutropenia, thrombocytopenia (with a higher bleeding risk) and anaemia; anaemia usually appears only after several cycles. The lowest leukocyte and platelet counts are usually seen in weeks 1 and 2, and blood values normally recover in about 20 days.

Serious reactions to watch for include haemorrhagic cystitis (very rarely fatal) and bladder fibrosis; cardiotoxicity (myocarditis, heart failure, arrhythmias, very rarely fatal); lung toxicity (pneumonitis and fibrosis, which can appear years after treatment); hepatic veno-occlusive disease; severe or fatal infections, including reactivation of latent infections; anaphylactic reactions; hyponatraemia with water intoxication and a syndrome resembling SIADH; severe skin reactions; and secondary cancers, which can appear several years after treatment.

Combinations that raise the likelihood or severity of toxic effects, through pharmacodynamic or pharmacokinetic interactions, need an individual benefit–risk assessment and close monitoring. Patients who take medicines that reduce the activation of cyclophosphamide are monitored for loss of effect and for the need to adjust the dose. The SmPC lists further interacting medicines, so the prescriber and pharmacist review every co-medication.

• Medicines that slow activation (possible loss of efficacy): aprepitant; bupropion (an antidepressant); busulfan; ciprofloxacin; chloramphenicol; and triazole antifungals such as fluconazole and itraconazole, which inhibit cytochrome P450 and so the metabolism of cyclophosphamide.
• Busulfan: high-dose cyclophosphamide given less than 24 hours after high-dose busulfan may be cleared more slowly and have a longer half-life, which can raise the incidence of hepatic veno-occlusive disease and mucositis. Previous or concurrent busulfan also raises the risk of haemorrhagic cystitis.
• Fluoroquinolone antibiotics: ciprofloxacin and similar antibiotics given before cyclophosphamide, especially before bone marrow transplantation, can reduce its effect and allow the underlying disease to relapse.
• Chloramphenicol: prolongs the half-life of cyclophosphamide and delays its metabolism.
• Other myelosuppressive treatment and radiotherapy: more severe myelosuppression is expected in patients who were treated before or who receive chemotherapy or radiotherapy at the same time, and the dose may need to be reduced.
• Cardiotoxic treatment: the risk of cardiotoxicity rises with anthracyclines, pentostatin and previous radiotherapy to the heart region.
• Bladder radiotherapy: previous or concurrent radiation of the bladder raises the risk of haemorrhagic cystitis.
• Insulin and other glucose-lowering medicines: cyclophosphamide may interact with them, so caution is advised in people with diabetes.
• Alcohol: can increase chemotherapy-induced nausea and vomiting.
• Food and drink: drinking plenty of fluids is part of treatment (the SmPC asks for an adequate amount during and after each dose; DrugBank suggests 2 to 3 litres a day). DrugBank also notes that taking tablets with food can reduce stomach irritation.

Cyclophosphamide should be given only where facilities exist for regular monitoring of clinical, biochemical and haematological parameters before, during and after administration, and under the direction of an oncology specialist service. The powder for injection or infusion is given only by physicians experienced in cancer chemotherapy. The dose and duration depend on the indication, the combination regimen, the patient’s general health and organ function, and laboratory results, in particular blood counts. The dosage recommendations relate mainly to single-agent use; combined with other cytostatics of similar toxicity, a lower dose or longer treatment-free intervals may be needed. Colony-stimulating factors and erythropoiesis-stimulating agents can be considered to reduce myelosuppressive complications or to help deliver the planned dose.

Because activation needs liver metabolism, oral and intravenous administration are preferred. During or immediately after each dose, enough fluid is drunk or infused to force diuresis and lower the risk of urothelial toxicity, so cyclophosphamide is given in the morning.

Recommended Doses

• Coated tablets, continuous treatment: the general scheme is 50–200 mg of cyclophosphamide daily (1 to 4 tablets of 50 mg); more tablets can be taken if necessary. The physician decides according to current treatment guidelines.
• Injection or infusion, continuous treatment (adults and children): 3–6 mg/kg body weight daily (120–240 mg/m² body surface area).
• Injection or infusion, intermittent treatment (adults and children): 10–15 mg/kg (400–600 mg/m²) at intervals of 2 to 5 days.
• Injection or infusion, high-dose intermittent treatment (adults and children): 20–40 mg/kg (800–1,600 mg/m²) at intervals of 21 to 28 days.
• Haematopoietic stem cell transplantation: higher doses can be used, 60 mg/kg a day for 2 days. Mesna rescue and adequate hydration are then mandatory to prevent haemorrhagic cystitis.
• Duration: cycles of an intermittent regimen can be repeated every 3–4 weeks. The duration of treatment and of the intervals depends on the indication, the combination protocol, general health, laboratory results and recovery of the blood count.

Dose Adjustments

• Myelosuppression: leukocytes above 4,000/µL and platelets above 100,000/µL, 100% of the intended dose; leukocytes 2,500–4,000/µL and platelets 50,000–100,000/µL, 50% of the intended dose; leukocytes below 2,500/µL and platelets below 50,000/µL, postpone until the counts normalise or decide individually.
• Combination with other myelosuppressive medicines: a dose reduction may be needed, and the doses of the cytostatics are kept to the minimum. For the other cytotoxic medicines, consult their own dose-adjustment tables based on the blood count at the start of the cycle.
• Hepatic impairment: use in patients with liver impairment before treatment is assessed case by case. Severe hepatic impairment requires a dose reduction, and a 25% reduction is recommended when serum bilirubin is 3.1 to 5 mg/100 mL.
• Renal impairment: a 50% dose reduction is recommended when creatinine clearance is below 10 mL/min.

Special Populations

• Children and adolescents: doses similar to those recommended for adults are used, based on established treatment regimens.
• Elderly and debilitated patients: the dose is chosen with caution, taking into account the higher frequency of impaired liver, kidney or heart function, concomitant disease and treatment with other medicines.
• Renal and hepatic impairment: see Dose Adjustments.

Method of Administration

• Coated tablets: taken by mouth in the morning, swallowed whole, with enough liquid during or immediately after the dose.
• Powder for injection or infusion: given intravenously after reconstitution to 20 mg/mL (volumes are given in SmPC section 6.6). The reconstituted or diluted solution can be used for up to 24 hours, kept at or below 8 °C.

Cytotoxic Handling

Cyclophosphamide is a cytotoxic medicine. It is prepared, handled and disposed of according to local requirements for cytotoxic medicines. Vials of powder in which the active substance has melted must be discarded (see Storage Conditions).

Bone Marrow Suppression, Immunosuppression and Infections

• Myelosuppression and immunosuppression: cyclophosphamide can cause leukopenia, neutropenia, thrombocytopenia (with a higher risk of bleeding) and anaemia, together with marked suppression of the immune response. Severe immunosuppression has led to serious and sometimes fatal infections, including pneumonia, sepsis, septic shock, and bacterial, fungal, viral and parasitic infections. Latent infections can be reactivated, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leukoencephalopathy (also fatal), Pneumocystis jirovecii, herpes zoster and Strongyloides.
• Management: infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in neutropenia at the physician’s discretion, and febrile neutropenia needs antibiotics and/or antifungals. Cyclophosphamide may be unsuitable, or may have to be interrupted or reduced, in patients with a serious infection.
• When not to give it: unless essential, it is not given when leukocytes are below 2,500/µL and/or platelets below 50,000/µL. It is used with caution in severe bone marrow impairment and severe immunosuppression.
• Timing: falls in blood counts, and the time to recover, tend to increase with higher doses. Marked myelosuppression is expected in patients treated before or who receive chemotherapy or radiotherapy at the same time.
• Monitoring: strict haematological control is indicated in all patients. Leukocyte counts are done before each administration and regularly during treatment, every 5–7 days at first and every 2 days if the count falls below 3,000/mm³. Platelet and haemoglobin values are taken before each administration and at suitable intervals afterwards.

Urinary Tract and Kidney Toxicity

• Bladder and urinary tract: haemorrhagic cystitis, pyelitis, ureteritis and haematuria have been reported, and secondary bladder tumours with ulceration or necrosis, fibrosis and contracture can develop. Urotoxicity can occur with short-term and long-term use and after single doses, has been fatal, and can require stopping treatment. Cystectomy may be needed for fibrosis, bleeding or secondary cancer. Previous or concurrent bladder radiation, or treatment with busulfan, raises the risk.
• Before and during treatment: urinary tract obstruction must be excluded or corrected before starting. The urine sediment is checked regularly for red cells and other signs of uro- or nephrotoxicity. Use with caution in active urinary tract infection.
• Protection: mesna or intensive hydration can markedly reduce the frequency and severity of bladder toxicity, and patients should empty the bladder at regular intervals. Haematuria usually clears within a few days of stopping but may persist, and severe haemorrhagic cystitis normally means stopping treatment.
• Kidney and water balance: nephrotoxicity, including renal tubular necrosis, has been associated with cyclophosphamide. Hyponatraemia with increased total body water, water intoxication and a syndrome resembling SIADH (inappropriate antidiuretic hormone secretion) have been reported, some fatal.

Cardiotoxicity

Myocarditis and myopericarditis, which can come with pericardial effusion and cardiac tamponade, have caused severe and sometimes fatal congestive heart failure. Acute cardiac toxicity has been reported after a single dose of less than 20 mg/kg. Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation with ventricular tachyarrhythmia) have occurred with or without other signs of cardiotoxicity. The risk rises with high doses, older age, previous radiotherapy to the cardiac region, and previous or concurrent cardiotoxic agents. Special caution is needed in patients with risk factors or pre-existing heart disease.

Pulmonary Toxicity

Interstitial pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of lung toxicity have been reported and can lead to respiratory failure. The incidence is low, but the outlook for affected patients is poor. Late-onset pneumonitis (more than 6 months after the start of treatment) seems to carry a particularly high mortality, and pneumonitis can develop years after treatment. Acute lung toxicity has followed a single dose.

Hepatic Veno-Occlusive Disease

Hepatic veno-occlusive disease has been reported, including fatal cases. A conditioning regimen before bone marrow transplantation that combines cyclophosphamide with whole-body irradiation, busulfan or other agents is an important risk factor. It occurs in about 15–50% of patients who receive high-dose cyclophosphamide with busulfan or whole-body radiotherapy for allogeneic transplantation, and very rarely with high-dose cyclophosphamide alone in aplastic anaemia. The syndrome typically appears within 1 to 3 weeks with sudden weight gain, painful hepatomegaly, ascites, raised bilirubin and jaundice, and can progress to hepatorenal syndrome and multi-organ failure. Gradual development has also been reported with long-term low-dose immunosuppressive use. Risk factors include pre-existing liver impairment, previous abdominal radiotherapy and poor performance status.

Secondary Malignancies

As with all cytotoxic treatment, cyclophosphamide carries a risk of secondary tumours and their precursors as late sequelae. The risk of urinary tract cancer and of myelodysplastic changes, some progressing to acute leukaemia, is increased. Lymphoma, thyroid cancer and sarcomas have also been reported. Secondary cancers can develop several years after chemotherapy has ended, and after exposure in the womb. The risk of bladder cancer can be reduced considerably by preventing haemorrhagic cystitis.

Anaphylaxis, Wound Healing and Other Precautions

• Anaphylaxis: anaphylactic reactions, including fatal cases, have been reported, and cross-reactions with other alkylating agents are possible.
• Wound healing: cyclophosphamide can interfere with normal wound healing.
• Hair loss, nausea and mouth sores: alopecia is very common and dose-dependent and can progress to baldness; hair may grow back with a different texture or colour. Current antiemetic guidelines should be followed for nausea and vomiting, and alcohol can make them worse. Stomatitis (oral mucositis) can occur, and current guidance on prevention and relief should be followed.
• Renal impairment: reduced renal excretion, especially in severe impairment, can raise levels of cyclophosphamide and its metabolites and so increase toxicity.
• Hepatic impairment: severe impairment can reduce activation of cyclophosphamide and alter efficacy.
• Acute porphyria: cyclophosphamide is porphyrinogenic, so patients with acute porphyria are treated with caution.
• Adrenalectomised patients: patients with adrenal insufficiency may need a higher corticosteroid replacement dose under the stress of cytostatic toxicity.
• Diabetes: caution, because cyclophosphamide may interact with insulin and other glucose-lowering medicines.

Pregnancy, Breastfeeding and Fertility

• Genotoxicity and contraception: cyclophosphamide is genotoxic and mutagenic in somatic cells and in male and female germ cells. Women must avoid becoming pregnant during treatment and for 12 months afterwards, and men must avoid fathering a child during treatment and for 6 months afterwards. Sexually active men and women use effective contraception during these periods. Animal data suggest that exposure of oocytes during follicle development can lower implantation and viable pregnancy rates and raise the risk of malformation, and follicular development in humans may last more than 12 months.
• Pregnancy test: treatment must not be started in women of childbearing potential unless a pre-treatment pregnancy test is negative.
• Pregnancy: contraindicated. Malformations have been reported in children born to mothers treated in the first trimester, although children without malformations have also been born. Exposure in the womb can cause miscarriage, foetal growth retardation and foetotoxic effects in the newborn (leukopenia, anaemia, pancytopenia, severe bone marrow hypoplasia, gastroenteritis). Women are told of the risk of serious foetal damage in the first trimester. After the first trimester, if treatment cannot be delayed, the SmPC allows chemotherapy to start once the patient has been told of the slight but possible teratogenic risk and the potential risk to the foetus.
• Breastfeeding: cyclophosphamide passes into human milk, and neutropenia, thrombocytopenia, low haemoglobin and diarrhoea have been reported in breastfed infants of treated mothers. It is contraindicated during breastfeeding.
• Fertility: cyclophosphamide interferes with oogenesis and spermatogenesis and may cause sterility in both sexes, depending on the dose, the duration of treatment and gonadal function at the time. Sterility can be irreversible in some patients. Men should be told about sperm preservation before treatment.
• Women: transient or permanent amenorrhoea with raised gonadotropins and lowered oestrogen is common and is more often permanent in older women. Girls treated before puberty usually develop normal secondary sexual characteristics and regular periods and can conceive later, but those who keep ovarian function have a higher risk of premature menopause (before age 40).
• Men: oligospermia or azoospermia with raised gonadotropin and normal testosterone secretion can develop, with some testicular atrophy; potency and libido are normally unaffected. Azoospermia is reversible in some patients, sometimes only after several years, and men made sterile by cyclophosphamide have later fathered children.

Lactose and Sucrose

The coated tablets contain lactose and sucrose. Patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take them, and neither should patients with hereditary fructose intolerance or sucrase-isomaltase insufficiency.

Effect on Driving

Nausea and vomiting, dizziness, blurred vision and other visual disturbances can impair the ability to drive and use machines. The doctor decides in each case whether the patient may drive or use machinery.

Genoxal coated tablets: store below 25 °C in the original package, which protects them from light. Avoid direct sunlight and heat sources, which can change the appearance of the tablets without affecting the active substance.

Powder for injection or infusion: do not store above 25 °C, and keep in the original package to protect from light. Temperature during transport and storage can melt the active substance. Vials with melted content are easy to recognise: melted cyclophosphamide is a clear or yellowish viscous liquid, seen as a separate phase or as droplets in the vial. Such vials must be discarded. No refrigeration is required, but temperature excursions above the labelled limit should be avoided in transport for this reason. For storage after reconstitution or dilution, see Shelf Life.

3 years for the coated tablets and for the unopened powder for injection or infusion. After reconstitution, both the reconstituted and the diluted solution can be used for up to 24 hours (do not store above 8 °C).

Prescription only (Rx). Cyclophosphamide is used under the direction of an oncology service by physicians experienced in cancer chemotherapy, where facilities exist for regular clinical, biochemical and haematological monitoring. The powder for injection or infusion is supplied to the hospital or clinic that administers it. The coated tablets are taken by the patient, so they are supplied to the patient or to the treating clinic on prescription. As a cytotoxic medicine it is handled and disposed of under local cytotoxic rules, and heat exposure during transport is avoided because the powder can melt.