楷莱CAELYX

【 Function and Indication 】
Kailai CAELYX can be used for patients with low CD4(<200CD4 lymphocytes /mm3) and AIDS-related Kaposi sarcoma (AIDS-KS) with extensive skin, mucous membrane and visceral diseases.
This product can be used as a first-line systemic chemotherapy drug, or as a second-line chemotherapy drug to treat AlDS-KS patients with progressive disease, and can also be used for patients who cannot tolerate the combined chemotherapy of more than two drugs: vincristine, bleomycin and doxorubicin (or other anthracycline antibiotics).

Doxorubicin hydrochloride for injection, another indication is that Doxorubicin is an antimitotic cytotoxic drug, which can successfully induce remission of various malignant tumors, including acute leukemia, lymphoma, soft tissue and osteosarcoma, childhood malignant tumors and adult solid tumors, especially for breast cancer and lung cancer.

“Model and specification”
20mg/10mg，2mg/ml。

【 Usage and dosage 】
When preparing the liquid medicine, the contents of each vial are dissolved with 5ml of water for injection or sodium chloride injection. After adding the dissolving solution, gently shake the vial for half a minute to dissolve the contents, but do not turn the vial upside down.
Adults and children
[Intravenous Administration]: This is the most commonly used route of administration. The prepared solution is infused intravenously through an unobstructed infusion tube for about 2-3 minutes. This can reduce the risk of thrombosis and cellulitis and blisters caused by drug spillage. Common solutions are sodium chloride injection, 5% glucose injection, or sodium chloride glucose injection. Dose is usually calculated based on body surface area. Usually, when doxorubicin is used as a single drug, it is administered once every three weeks at a dose of 60-75 mg/m [sup] 2 [/sup]. When it is combined with other anticancer agents with overlapping toxicity, the dose of doxorubicin should be reduced to once every three weeks, and it should be administered at a dose of 30-40 mg/m [sup] 2 [/sup]. If the dose is calculated according to body weight, it should be given once every three weeks at a single dose of 1.2-2.4 mg/kg. It has been proved that a single dose once every three weeks can greatly reduce the painful toxic reaction and mucositis. However, some people still think that three days’ dose (0.4-0.8 mg/kg or 20-25 mg/m [sup] 2 [/sup] per day) will produce greater therapeutic effect, although the drug toxicity will be higher. The weekly regimen of doxorubicin is as effective as the regimen of once every three weeks. Although effective relief has been observed at the dose of 6-12 mg/m [sup] 2 [/sup], the recommended dose for weekly administration is 20mg/m[sup]2[/sup]. Weekly administration can reduce cardiotoxicity. Patients who have previously used other cytotoxic drugs may need to reduce their dosage, as well as children and the elderly.
If liver and kidney function is impaired, the dosage of doxorubicin should be reduced according to the following table:
Serum bilirubin level BSP retention recommended dose
1.2-3.0mg/100ml 9-15% 50% of the normal dose.
] 3.0mg/100ml] 15％% 25% of the normal dose.

[Intra-arterial medication]: Intra-arterial injection is usually used to enhance local activity and reduce the total dose, thus reducing systemic toxicity. It must be emphasized that this method of administration has great potential damage, and unless appropriate preventive measures are taken, the perfused tissue will produce extensive necrosis.

Intra-arterial injection can only be used by skilled personnel.

Intravesical instillation: Intravesical instillation of doxorubicin is increasingly used in the treatment of transitional cell carcinoma, papillary cystoma and carcinoma in situ. It can not be used for the treatment of invasive tumors that have penetrated the bladder wall. Intermittent intravesical instillation of doxorubicin after transurethral resection of tumor has been proved to effectively reduce the possibility of recurrence. At present, there are many schemes in use, and it is difficult to explain them one by one. The following instructions may be helpful.

The concentration of doxorubicin in bladder should be 50mg/50ml. In order to avoid improper dilution of urine, patients should be told not to take any liquid 12 hours before perfusion. The urine volume should be limited to about 50ml per hour. When the medicine stays in one place for 15 minutes, the patient should turn 90 degrees. Usually, one hour of contact with the medicine is enough, and the patient should be told to urinate at the end.

[Adjuvant therapy] In a large-scale randomized study conducted by National Breast and Intestinal Surgery Adjuvant Therapy Project (NSABP) B-15, patients with early breast cancer with positive axillary lymph nodes were given AC combined chemotherapy, that is, doxorubicin 60mg/m[sup]2[/sup] and cyclophosphamide 600mg/m[sup]2[/sup] were given on the first day of the treatment cycle.

About 2300 patients with early breast cancer with axillary lymph node positive (80% of them are premenopausal women and 20% are postmenopausal women) participated in a randomized, open and multicenter clinical study (NSABP B-15) in the largest meta-analysis of EBCTCG consisting of six studies. In this study, we compared the curative effects of 6 cycles of conventional CMF therapy, 4 cycles of AC therapy and 4 cycles of AC therapy followed by 3 cycles of CMF therapy, and there was no significant difference in the disease-free survival and overall survival of three years. However, the results of quality of life items (such as administration times and treatment cycle) are better than the combined treatment scheme of CMF and AC. In addition to the quality of life, the adverse reactions of 2-month AC treatment plan are also lower than those of 6-month CMF conventional treatment plan.

[Clinical research]
The exact anti-tumor mechanism of doxorubicin is not clear. It is generally believed that it has cytotoxic effect on inhibiting DNA, RNA and protein synthesis. This is because this anthracycline antibiotic can be embedded between adjacent base pairs of DNA double helix, thus inhibiting its replication after melting.
The toxicity of this product in the study of multi-dose administration to animals is similar to the result of long-term drip of doxorubicin hydrochloride in human body. This product encapsulates doxorubicin hydrochloride and hides it in liposomes, so the degree of its toxic reaction is different:
Cardiotoxicity: Studies in rabbits show that the cardiotoxicity of this product is lower than that of ordinary doxorubicin hydrochloride preparations.
Cutaneous toxicity: In repeated dosing tests in rats and dogs, severe skin inflammation and ulcer formation can be seen at a dose equivalent to clinical application. In the study of dogs, reducing the dosage or extending the interval of administration can reduce the incidence and severity of these injuries. Similar skin damage can also be seen in patients who have been given drugs by intravenous drip for a long time, such as erythema of palm and sole.
Allergic reaction: in the toxicological study of repeated administration in dogs, the following acute reactions can be seen after administration of liposome (placebo): hypotension, pale mucosa, salivation, vomiting, decreased activity after excessive activity and drowsiness. Similar but not serious reactions can be seen in dogs using this product and doxorubicin. Pre-administration of antihistamine can reduce the hypotension reaction. However, this reaction is not life-threatening, and the dog can quickly return to normal after stopping the drug.
Local toxicity: The subcutaneous tolerance test showed that compared with doxorubicin hydrochloride, this product had less local irritation or damage under the condition of extravasation of liquid medicine.
Mutagenicity and carcinogenicity: Although this product has not been studied, doxorubicin hydrochloride, the pharmacologically active component of this product, has mutagenicity and carcinogenicity. Liposome (placebo) has no mutagenic and carcinogenic effects.
Reproductive toxicity: A single dose of this product (36mg/kg) in mice caused mild to moderate ovarian or testicular atrophy. Repeated administration (≥0.25mg/kg/ day) in rats will lead to the decrease of testicular weight and sperm loss. After repeated administration (1mg/kg/ day), diffuse degeneration of seminiferous tubules and significant decrease of sperm were observed in dogs.

【 Precautions 】
1. If the drug overflows during the administration, it will lead to serious local tissue necrosis (see usage and dosage). Doxorubicin should not be injected intramuscularly or subcutaneously.
2. Myocardial toxicity may occur during the treatment of doxorubicin and several months to several years after stopping the treatment, and the most serious myocardial toxicity is potentially fatal congestive heart failure. The possibility of myocardial dysfunction is based on a series of symptoms and signs. When the total cumulative dose of doxorubicin reaches 300 mg/m2, the left ventricular ejection fraction (LVEF) decreases by about 1-2%, by about 3-5% when it reaches 400 mg/m2, by about 5-8% when it reaches 450 mg/m2, and by about 6-20% when it reaches 500 mg/m2. When the total cumulative dose exceeds 400 mg/m2, the risk of congestive heart failure increases rapidly. Risk factors (active or inactive cardiovascular disease, previous or simultaneous radiotherapy of mediastinum/pericardiac region, previous treatment with other anthracyclines or anthracenediones, and use of other cardiotoxic drugs) may increase the risk of cardiotoxicity. Whether there are risk factors or not, doxorubicin may still have cardiotoxicity at a low cumulative dose. After using doxorubicin in pediatric patients, the risk of delayed cardiotoxicity increases.
3. It has been reported that secondary acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) occurred in patients treated with anthracyclines including doxorubicin (see adverse reactions). Refractory and secondary AML or MDS will be more common when anthracyclines are used in combination with anti-tumor agents that destroy DNA structure or radiotherapy in patients who have received high-dose cytotoxic drugs or patients who have increased the dosage of anthracyclines. The incidence of secondary AML or MDS was evaluated in 8563 patients with early breast cancer in 6 clinical studies (including NSABP-15 study) of National Breast and Intestinal Surgery Adjuvant Treatment Project (NSABP). These patients received standard dose of doxorubicin and standard or high dose of cyclophosphamide as adjuvant chemotherapy, and 61,810 patients were followed up within several years. Among 4483 patients treated with cyclophosphamide, 11 patients developed secondary AML or MDS, the incidence rate was 0.32/1000 patients/year (95 95% CI, 0.16-0.57), and the cumulative incidence rate in five years was 0.21% (95% CI, 0.11–0.41%). In addition, the incidence of secondary AML or MDS in 10 years was about 1.5% among 1474 breast cancer patients who received adjuvant therapy with doxorubicin in Anderson Cancer Center of Texas University School of Medicine. In the above two studies, patients who received high-dose cyclophosphamide and radiotherapy or patients over 50 years old had an increased risk of secondary AML or MDS. Pediatric patients are also at risk of secondary AML.
4. Patients with impaired liver function should reduce the dosage.
5. May lead to severe bone marrow suppression.
6. Doxorubicin should be used under the guidance of a doctor with experience in the use of tumor chemotherapy drugs.

General rule: Doxorubicin must be used under the guidance of a doctor who has experience in using cytotoxic drugs.

Before the treatment of doxorubicin, the patient should have recovered from the acute toxic reactions (such as stomatitis, neutropenia, thrombocytopenia and systemic infection) of previous cytotoxic drugs.

The systemic clearance rate of doxorubicin in obese patients is decreased.

Cardiac function: The use of anthracycline drugs has the risk of cardiotoxicity, which is manifested as early (i.e. acute) or late (i.e. delayed) events.

Early events: The early cardiotoxicity of doxorubicin mainly includes sinus tachycardia and/or abnormal electrocardiogram (ECG), such as nonspecific ST-T wave changes. Tachycardia, including ventricular premature beats, ventricular tachycardia, bradycardia, and atrioventricular and bundle branch block have been reported. These adverse events usually have no predictive effect on the subsequent delayed cardiotoxicity, and have little clinical significance, and there is usually no need to stop the treatment of doxorubicin.

Late (i.e. delayed) events: Delayed cardiotoxicity usually occurs in the late stage of doxorubicin treatment or 2 to 3 months after treatment termination. However, there are also reports of delayed events that occur months to years after the end of treatment. Delayed cardiomyopathy can be manifested as symptoms and signs of decreased left ventricular ejection fraction (LVEF) and/or congestive heart failure (CHF), such as dyspnea, pulmonary edema, dropsy, cardiac hypertrophy, hepatomegaly, oliguria, ascites, pleural effusion and galloping rhythm. There are also reports of subacute symptoms, such as pericarditis/myocarditis. The most serious cardiomyopathy caused by anthracyclines is life-threatening congestive heart failure, which shows cumulative dose-limiting toxicity.

Before the treatment with doxorubicin, it is necessary to evaluate the cardiac function, and it is necessary to monitor the cardiac function during the whole treatment to minimize the risk of serious cardiac function damage. The left ventricular ejection fraction (LVEF) should be monitored regularly during the treatment, and doxorubicin should be stopped immediately once the symptoms of cardiac function damage appear, which can reduce the risk of cardiotoxicity. MUGA scan (multi-gated radionuclide angiography) or ECHOcardiogram (echo) can be used for repeated quantitative evaluation of cardiac function (evaluation of LVEF). ECG, MUGA scan or ECHO examination at baseline is recommended, which is especially suitable for patients with high risk factors. MUGA scan or ECHO examination should be repeated to evaluate left ventricular ejection fraction, especially when using high cumulative dose of anthracyclines. such
Evaluation techniques should also be used consistently during follow-up. During the follow-up, the detection methods used to monitor cardiac function should be consistent.

When the cumulative dose is 300 mg/m2, the probability of CHF is about 1% ~ 2%, and it will increase slowly with the cumulative dose increasing to 450-550 mg/m2. After that, the risk of CHF will increase rapidly, so it is suggested that the maximum cumulative dose should not exceed 550 mg/m2.

Risk factors of cardiotoxicity include active or inactive cardiovascular disease, current or past radiotherapy of mediastinum/pericardiac region, previous use of other anthracyclines or anthracenediones, and simultaneous use of other drugs that inhibit myocardial contraction or drugs with cardiotoxicity (such as trastuzumab). Anthracyclines, including doxorubicin, cannot be used with other cardiotoxic drugs unless the patient’s cardiac function is closely monitored. Patients receiving anthracyclines after stopping using other drugs with cardiotoxicity (especially drugs with long half-life such as trastuzumab) may also increase the risk of cardiotoxicity. The half-life of trastuzumab is about 28.5 days and can last up to 24 weeks in blood circulation. Therefore, if possible, doctors should avoid using anthracycline-based treatment within 24 weeks after stopping trastuzumab. If anthracycline drugs need to be used before this time, the heart function should be closely monitored.

Patients who receive high cumulative dose of doxorubicin and have high risk should be strictly monitored for cardiac function. However, whether there are risk factors of cardiotoxicity or not, cardiotoxicity may still occur when the cumulative dose is low.

Children and adolescents are at increased risk of developing delayed cardiotoxicity after using doxorubicin. The risk of delayed cardiotoxicity in female patients may be higher than that in male patients. Regular cardiac function assessment is recommended to monitor the possibility of this toxicity.

The toxic effects of doxorubicin and other anthracyclines or anthracenediones may be cumulative.

Hematological toxicity: When combined with other cytotoxic drugs, doxorubicin can cause bone marrow suppression. Hematological examination, including white blood cell (WBC) count, should be performed before using doxorubicin and every cycle. Dose-dependent, reversible leukopenia and/or neutropenia (neutropenia) are the main hematological toxicity of doxorubicin and the most common acute dose-limiting toxicity of doxorubicin. Leukopenia and neutropenia generally reach the lowest point 10 to 14 days after medication. The white blood cell/neutrophil count of most patients will return to the normal range within 21 days. Thrombocytopenia and anemia may also occur. Clinical manifestations of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia and even death.

Secondary leukemia: There are reports of secondary leukemia in patients treated with anthracyclines including doxorubicin, with or without pre-leukemia symptoms. Secondary leukemia is more common in the following cases: when it is used in combination with anticancer drugs whose mechanism is to destroy DNA structure, or when it is combined with radiotherapy, or when the patient has used cytotoxic drugs many times before, or when the therapeutic dose of anthracycline drugs increases. The incubation period of this kind of leukemia is usually 1 ~ 3 years.

Gastrointestinal tract: Doxorubicin can cause vomiting reaction. Stomatitis/mucositis usually occurs in the early stage after administration, and if the situation is serious, it may progress to mucosal ulcer after a few days. The vast majority of patients recovered in the third week after administration.

Patients with acute non-lymphocytic leukemia who use doxorubicin and cytarabine combined chemotherapy for 3 consecutive days may suffer from colon ulcer and necrosis, and die from bleeding or infection.

Liver function: Doxorubicin is mainly cleared through the hepatobiliary system. The serum total bilirubin level should be evaluated before and during medication. Patients with elevated bilirubin may have slow drug clearance and increased systemic toxicity. These patients need to be reduced. Patients with severe liver damage cannot receive doxorubicin treatment.

Injection site reaction: intravenous injection or repeated injection of the same vein may cause venous sclerosis, and the occurrence of phlebitis/thrombophlebitis at the injection site can be reduced as much as possible by following the recommended administration process.

Drug extravasation: extravasation of doxorubicin during intravenous injection will lead to local pain, serious tissue damage (blistering, severe cellulitis) and necrosis. Once the symptoms and signs of extravasation occur during injection, the injection should be stopped immediately.

Tumor lysis syndrome: the use of doxorubicin may lead to hyperuricemia, which is caused by excessive purine catabolism (tumor lysis syndrome) accompanied by the rapid disintegration of tumor cells induced by drugs. Therefore, it is necessary to monitor blood uric acid, potassium, calcium, phosphorus and creatinine after the initial treatment. Hydration, alkalization of urine and preventive use of allopurinol can prevent hyperuricemia, thus reducing the occurrence of tumor lysis syndrome as much as possible.

Immunosuppressive effect/increased susceptibility to infection: Inoculation of live vaccine or attenuated live vaccine may cause serious or even fatal infection for patients whose immune compromise is caused by chemotherapy drugs including doxorubicin. Patients who are receiving doxorubicin should avoid receiving live vaccine. Dead or inactivated vaccines can be inoculated, but the immune response to these vaccines may be reduced.

Intravesical administration: Be especially careful when using this product in the bladder. Intravesical administration of doxorubicin may cause symptoms related to chemical cystitis (such as dysuria, polyuria, nocturia, painful urinary leaching, hematuria, bladder discomfort, bladder wall necrosis) and bladder spasm. Special attention should be paid to the problem of intubation (such as urethral obstruction caused by huge tumor in bladder).

It is suggested that correct urethral irrigation should be given immediately during the administration and after the liquid medicine is emptied from the bladder.

Others: Doxorubicin can aggravate the toxic reaction of other anti-tumor drugs. It has been reported that it can aggravate hemorrhagic cystitis caused by cyclophosphamide and hepatotoxicity of 6- mercaptopurine. It is also reported that it can increase the toxic reactions caused by radiotherapy (such as myocardial, mucosal, skin and liver damage).

It has been reported that when combined with other cytotoxic drugs, patients who use doxorubicin have thrombophlebitis and thromboembolism, including pulmonary embolism (some of which are fatal).

Like most cytotoxic drugs and immunosuppressants, this product has been observed to be carcinogenic to animals under certain experimental conditions.

Doxorubicin can make urine red 1-2 days after administration.

Matters needing attention during operation:
The medicine in the bottle is in a negative pressure state, so as to reduce the aerosol formed when the solution is prepared, and special care should be taken when the needle is inserted. Avoid inhaling any aerosol when preparing liquid medicine.

Due to the toxicity characteristics of this drug, the following protection methods are recommended:
-Operators must have good technical training in drug preparation and operation.
-Pregnant workers should avoid touching this product.
-Operators of instant doxorubicin should wear protective clothing: goggles, gowns, disposable gloves and masks.
-Drug preparation should be carried out in the designated area (preferably in laminar flow system). The surface of the workbench should be covered with disposable absorbent paper with plastic coating on the back.
-All materials used for drug preparation, injection or cleaning, including gloves, should be placed in waste bags marked “highly dangerous” for high-temperature incineration after use.
-In case of accidental contact with skin or eyes, the skin at the contact area should be thoroughly washed with soap and water immediately, and the eyes should be washed with sodium bicarbonate solution. And consult a doctor.
-If the liquid medicine oozes or leaks, it should be treated with 1% sodium hypochlorite solution, and it is best to soak it overnight, and then rinse it with water.
-All cleaning materials should be treated according to the above method.

The prepared solution can be kept stable for 24 hours at room temperature and 48 hours at 4 ~ 10 C.
The prepared solution contains 0.02% hydroxybenzoate, but it can’t be regarded as a preservative solution.
Any surplus unused drugs and wastes should be discarded according to the requirements of local laws and regulations.

Important information about accessories
This product contains methyl paraben, which may cause allergic reaction (possibly delayed) and occasionally bronchospasm.
This product contains lactose, so patients with rare hereditary lactose intolerance, lactose enzyme deficiency and glucose-lactose absorption disorder should not use this product for treatment.

[Adverse reactions and contraindications]
Bone marrow suppression and cardiotoxicity are the two main adverse reactions of doxorubicin.
1. Skin and subcutaneous tissue damage: local toxicity, rash/itching, skin changes, hyperpigmentation of skin and nails, photosensitive reaction, skin irradiation allergy (radiation recall reaction), rubella, erythema of extremities, hand-foot syndrome, common hair loss, including beard growth stagnation, but all hairs can return to normal growth after stopping treatment.
2. In the study of early breast cancer patients receiving adjuvant therapy containing doxorubicin, in addition to the known adverse reactions of doxorubicin, patients were also observed to gain weight.
3. Infection: infection, sepsis/septicemia.
4. Benign and malignant tumors: acute lymphoblastic leukemia, acute myeloid leukemia.
5. Blood and lymphatic system damage: leukopenia, neutropenia, anemia, thrombocytopenia.
6. Immune system damage: allergic reaction.
7. Metabolic and nutritional imbalance: anorexia, dehydration, hyperuricemia.
8. Eye injury: conjunctivitis/keratitis, tears.
9. Vascular injury: hot flashes, phlebitis, thrombophlebitis, thromboembolism and shock.
10. Reproductive system and breast injury: menopause, oligospermia and azoospermia.
11. Systemic and local injuries at the administration site: discomfort/weakness, fever and chills.
12. Bone marrow suppression and oral ulcer: Do not use this product repeatedly when there is bone marrow suppression and oral ulcer. The latter may have premonitory symptoms of oral burning, and should not be used when symptoms appear. The obvious bone marrow suppression can appear about 10 days after the use of doxorubicin, so the hemogram should be routinely monitored in patients with hematological or non-hematological diseases.
13. Cardiotoxicity: Cardiotoxicity can be manifested as sinus tachycardia, tachycardia, atrioventricular block and bundle branch block, congestive heart failure, including supraventricular tachycardia and ECG changes. It is suggested that ECG should be monitored regularly, and patients with impaired cardiac function should be especially careful. When the cumulative dose exceeds 450－ 500mg/m2, the risk of irreversible congestive heart failure will be greatly increased. When considering the total dosage of doxorubicin, we should comprehensively evaluate the patients’ previous or simultaneous use of other drugs with obvious cardiotoxicity, such as high-dose intravenous cyclophosphamide, mediastinal radiotherapy or related anthracycline compounds such as daunorubicin. It has been proved that weekly administration of doxorubicin is less toxic to the heart than every three weeks, which allows patients to get a higher cumulative dose of treatment. It must be noted that heart failure can appear several weeks after medication and may not respond to treatment. It is suggested that the basic electrocardiogram should be detected and ECG follow-up should be done during and immediately after medication. Transient ECG changes, such as low T wave level, decreased S-T segment and arrhythmia, are not considered as indications to stop using drugs. Now it is considered that the decrease of QRS wave is a specific manifestation of cardiotoxicity. If this change occurs, we must carefully weigh the relationship between the benefits of continuing medication and the risk of irreversible heart damage. Severe heart failure can occur suddenly without ECG changes in advance.
14. Instant doxorubicin hydrochloride for injection can make the urine red, especially the urine discharged for the first time after injection. Patients should be informed that there is no need to panic.
15. Gastrointestinal reactions: nausea, vomiting, mucositis/stomatitis, oral mucosal pigmentation, esophagitis, abdominal pain, gastric mucosal injury, gastrointestinal bleeding, diarrhea and colitis may also occur.
16. Others: abnormal liver and kidney function.
17. Asymptomatic left ventricular ejection fraction decreased and transaminase level changed.

[taboo]
Severe organic heart disease and abnormal cardiac function, and those who are allergic to this product and anthracyclines are prohibited.
1. Contraindications for intravenous administration:
● Persistent bone marrow suppression or severe oral ulcer caused by previous cytotoxic drug treatment;
● Systemic infection;
● obvious liver function damage;
● Severe arrhythmia, insufficient myocardial function and previous myocardial infarction;
● The maximum cumulative dose of drugs used in anthracycline therapy in the past.

2. Contraindications for intravesical perfusion therapy:
● Invasive tumor has penetrated the bladder wall;
● Urinary tract infection;
● Bladder inflammation;
● Catheter insertion is difficult (e.g. due to huge bladder tumor).
● hematuria.

 

 

[Medication for pregnant women]
Pregnant women and lactating women are prohibited.

Fertility damage
During the medication, doxorubicin may cause infertility in female patients. Doxorubicin can also cause amenorrhea. Although doxorubicin can lead to early menopause, ovulation and menstruation may still recover after termination of treatment.

In male patients, doxorubicin has mutagenic effect and can damage chromosomes in human sperm. Oligozoospermia or azoospermia may be permanent, but it has been reported that in some cases the sperm count has returned to normal level. This may happen several years after the end of treatment. Male patients should take effective contraceptive measures during the treatment with doxorubicin.

pregnancy
In vivo and in vitro experiments confirmed that doxorubicin had potential embryotoxicity. Dosing doxorubicin before or during mating, pregnancy and lactation of female rats is toxic to both female rats and fetal rats.
When doxorubicin is used in pregnant women, it has caused fetal damage. If a female patient is treated with doxorubicin during pregnancy or becomes pregnant during medication, the patient must be informed of the potential harm of the drug to the fetus.

[Drug Interaction]
1. Doxorubicin is usually combined with other cytotoxic drugs, so there may be a superposition of toxic effects, especially bone marrow, hematology and gastrointestinal toxicity. In addition, if doxorubicin is used with other antineoplastic drugs that have been reported to have potential cardiotoxicity (such as 5-Fu, cyclophosphamide, cisplatin, etc.) or with other drugs with cardiac activity (such as calcium channel antagonists), it is necessary to closely monitor cardiac function during the whole treatment period.
2. The metabolism of doxorubicin is mainly in the liver, and other changes in liver function caused by concomitant therapy can affect the metabolism, pharmacokinetics, efficacy and/or toxicity of doxorubicin.
3. This product should avoid long-term contact with alkaline solution.
4. Because of precipitation, the instant doxorubicin should not be mixed with heparin, and it is not recommended to mix the instant doxorubicin with other drugs.
5. The use of paclitaxel before doxorubicin will increase the plasma concentration of doxorubicin and/or its metabolites. There is evidence that the above effects will be reduced when doxorubicin is used before paclitaxel.
6. In different clinical studies, when doxorubicin was combined with sorafenib (400mg, twice a day), the area under the concentration-time curve of doxorubicin increased (21%-47%), and the area under the concentration-time curve of doxorubicin remained unchanged. The clinical significance of these findings has not been confirmed.

[storage]
Store in the dark at room temperature.