Adriamycin

Name: Adriamycin

What Is Dox Orubicin?

Doxorubicin is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Doxorubicin is used to treat different types of cancers that affect the breast, bladder, ovary, thyroid, stomach, lungs, bones, nerve tissues, muscles, joints, and soft tissues. Doxorubicin is also used to treat Hodgkin's disease and certain types of leukemia.

Doxorubicin may also be used for purposes not listed in this medication guide.

You should not use this medication if you have an untreated or uncontrolled infection, severe liver disease, severe heart problems, or if you have recently had a heart attack.

Doxorubicin may cause dangerous effects on your heart. Call your doctor at once if you have chest pain, shortness of breath (even with mild exertion), swelling, or rapid weight gain.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when doxorubicin is injected. Call your doctor if you have irritation or skin changes where the injection was given.

Doxorubicin can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

Using doxorubicin may increase your risk of developing a bone marrow disease or other types of cancer, such as leukemia.

You should not use this medication if you are allergic to doxorubicin or similar medications (doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), or if you have:

  • an untreated or uncontrolled infection (including mouth sores);
  • severe liver disease;
  • severe heart problems; or
  • if you have recently had a heart attack.

To make sure doxorubicin is safe for you, tell your doctor if you have:

  • liver or kidney disease;
  • bone marrow suppression;
  • heart disease; or
  • if you have been treated before with doxorubicin, daunorubicin, epirubicin, idarubicin, or mitoxantrone.

Tell your doctor about all other cancer medicines or radiation treatments you have received in the past.

Using doxorubicin may increase your risk of developing a bone marrow disease or other types of cancer, such as leukemia. Ask your doctor about your specific risk.

Do not use doxorubicin if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

Doxorubicin can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using doxorubicin.

Adriamycin Overview

Adriamycin is a prescription medication used to treat certain types of cancer in adults and children including breast cancer, lung cancer, and ovarian cancer.  Adriamycin belongs to a group of drugs called anthracylines, which slow and stop the growth of cancer cells.

This medication comes in an injectable form and is given by injection into a vein (intravenously) by a healthcare provider.

Common side effects of Adriamycin include hair loss, nausea, and vomiting.

 

Uses of Adriamycin

Adriamycin is a prescription medication used in combination with other medications to treat:

  • certain types of bladder, breast, lung, stomach, and ovarian cancer
  • Hodgkin's lymphoma (Hodgkin's disease)
  • non-Hodgkin's lymphoma (cancer that begins in the cells of the immune system)
  • certain types of leukemia (cancer of the white blood cells), including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML, ANLL)
Adriamycin is also used alone and in combination with other medications to treat:
  • certain types of thyroid cancer
  • certain types of soft tissue or bone sarcomas (cancer that forms in muscles and bones)
  • neuroblastoma (a cancer that begins in nerve cells and occurs mainly in children)
  • Wilms' tumor (a type of kidney cancer that occurs in children)

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

 

 

Inform MD

Before you receive Adriamycin, tell your doctor if you:

  • have heart problems
  • have had radiation treatment or currently receiving radiation therapy
  • are over the age of 50
  • have liver problems
  • plan to receive any vaccines
  • have any other medical conditions
  • are pregnant or breastfeeding

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Adriamycin can interact with other medicines. Do not start any new medicine before you talk with the doctor that prescribed Adriamycin.

Adriamycin Dosage

Liposomal formulation (Lipodox):

  • Breast Cancer/Ovarian cancer: 50 mg/m2 once every 4 weeks
  • AIDS-KS patients: 20 mg/m2 once every 3 weeks

Liposomal formulation (Doxil):

  • Ovarian Cancer: 50 mg/m2 once every 4 weeks. A minimum of 4 courses is recommended.
  • AIDS-Related Kaposi's Sarcoma: 20 mg/m2 once every three weeks
  • Multiple Myeloma: 30 mg/m2 on day 4 following bortezomib therapy. You may be treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.

Adriamycin (doxorubicin) formulation:

  • The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m2 as a single injection. It is given at 21-day intervals.
  •  When used in combination with other chemotherapy drugs, the most commonly used dosage is 40 to 60 mg/m2 every 21 to 28 days.
  • The NSABP B-15 study: the combination dosage regimen of Adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2 was done on day 1 of each 21-day treatment cycle. Four cycles of treatment were completed.

Adriamycin Dosage and Administration

Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21 day treatment cycle, in combination with cyclophosphamide, for a total of four cycles [see Clinical Studies (14)].

Metastatic Disease, Leukemia, or Lymphoma

  • The recommended dose of doxorubicin when used as a single agent is 60 to 75 mg/m2 intravenously every 21 days.
  • The recommended dose of doxorubicin, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m2 intravenously every 21 to 28 days.
  • Consider use of the lower doxorubicin dose in the recommended dose range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients.
  • Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1)].

Dose Modifications

Cardiac Impairment

Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

Doxorubicin is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL) [see Contraindications (4 )].

Decrease the dose of doxorubicin in patients with elevated serum total bilirubin concentrations as follows:

 

Serum bilirubin concentration

 

Doxorubicin Dose reduction

 

1.2 to 3 mg/dL

 

50%

 

3.1 to 5 mg/dL

 

75%

 

greater than 5 mg/dL

 

Do not initiate doxorubicin

Discontinue doxorubicin

[seeWarnings and Precautions (5.5)  and Use in Specific Population (8.7)] 

Preparation and Administration

Preparation for Continuous Intravenous Infusion

Dilute doxorubicin solution or reconstituted solution in 0.9% Sodium Chloride Injection or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion.

Administration

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.

Storage of vials of Adriamycin (DOXOrubicin HCl) Injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15º to 30ºC (59º to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Administration by Intravenous Injection:

  • Administer doxorubicin as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose Injection.
  • Administer doxorubicin intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.

Administration by Continuous Intravenous Infusion:

  • Infuse only through a central catheter. Decrease the rate of doxorubicin administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
  • Protect from light from preparation for infusion until completion of infusion.

Management of Suspected Extravasation

Discontinue doxorubicin for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

  • Do not remove the needle until attempts are made to aspirate extravasated fluid.
  • Do not flush the line.
  • Avoid applying pressure to the site.
  • Apply ice to the site intermittently for 15 min 4 times a day for 3 days.
  • If the extravasation is in an extremity, elevate the extremity.
  • In adults, consider administration of dexrazoxane [see Warnings and Precautions (5.3)].

Incompatibility with Other Drugs

Do not admix doxorubicin with other drugs. If doxorubicin is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin.

Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin consistent with recommendations for the handling and disposal of hazardous drugs.1

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.

Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling.

  • Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1)]
  • Secondary Malignancies [see Warnings and Precautions (5.2)]
  • Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3)]
  • Severe Myelosuppression [see Warnings and Precautions (5.4)]
  • Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
  • Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7)]

Clinical Trial Experience in Breast Cancer

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data below were collected from 1492 women who received doxorubicin at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 1. No treatment-related deaths were reported in patients on either arm of the study.

 

Table 1. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes

 

Adverse reactions, % of patients

 

AC*

N=1492

 

Conventional CMF

N=739

 

Leukopenia

Grade 3 (1,000 to 1,999 /mm3)

Grade 4 (<1000 /mm3)

 

3.4

0.3

 

9.4

0.3

 

Thrombocytopenia

Grade 3 (25,000 to 49,999 /mm3)

Grade 4 (<25,000 /mm3)

 

0

0.1

 

0.3

0

 

Shock, sepsis

 

2

 

1

 

Systemic infection

 

2

 

1

 

Vomiting

Vomiting ≤12 hours

Vomiting >12 hours

Intractable

 

34

37

5

 

25

12

2

 

Alopecia

 

92

 

71

 

Cardiac dysfunction

Asymptomatic

Transient

Symptomatic

 

0.2

0.1

0.1

 

0.1

0

0

* Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of doxorubicin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac – cardiogenic shock

Cutaneous – Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia

Gastrointestinal – Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa

Hypersensitivity – Anaphylaxis

Laboratory Abnormalities –Increased alanine aminotransferase, increased aspartate aminotransferase

Neurological – Peripheral sensory and motor neuropathy, seizures, coma

Ocular – Conjunctivitis, keratitis, lacrimation

Vascular – Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism

Other – Malaise/asthenia, fever, chills, weight gain

Adriamycin Description

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var.caesius. Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. Chemically, doxorubicin hydrochloride is (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)-oxy]-8-glycoloyl-7,8,9,10-tetrahydro-

6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The structural formula is as

follows:

Doxorubicin binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins.

It is supplied in the hydrochloride form as a sterile parenteral, isotonic solution with sodium chloride for intravenous use only.

Adriamycin (DOXOrubicin HCI) Injection, USP:

Each 2 mg/mL, 5 mL (10 mg) vial contains 10 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 10 mL (20 mg) vial contains 20 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 25 mL (50 mg) vial contains 50 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 100 mL (200 mg) multiple dose vial contains 200 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Adriamycin - Clinical Pharmacology

Mechanism of Action

The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin cytocidal activity.

Pharmacokinetics

Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. The distribution half-life is approximately 5 minutes, while the terminal half-life is 20 to 48 hours. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 to 70 mg/m2 .

Distribution

Steady-state distribution volume ranges from 809 to 1214 L/m2. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 75% and is independent of plasma concentration of doxorubicin up to 1.1 mcg/mL.

Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m2 of doxorubicin given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours.

Doxorubicin does not cross the blood brain barrier.

Metabolism

Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin. Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5.

Excretion

Plasma clearance is in the range 324 to 809 mL/min/m2 and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days.

Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

Pediatric patients

Following administration of doses ranging from 10 to 75 mg/m2 of doxorubicin to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older children and approached the range of clearance values determined in adults [see Use in Specific Populations (8.4 )].

Patient Gender

There is no recommended dose adjustment based on gender. A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours).

Patients with hepatic impairment

The clearance of doxorubicin and doxorubicinol was reduced in patients with elevation in serum bilirubin [see Dosage and Administration (2.2 ) and Warnings and Precautions (5.5 )].

How Supplied/Storage and Handling

Adriamycin (DOXOrubicin HCI) Injection, USP is supplied in single-dose, fl ip-top vials, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strengths:

NDC 0143-9549-10: 10 mg in 5 mL; carton of 10.

NDC 0143-9548-10: 20 mg in 10 mL; carton of 10.

NDC 0143-9547-01: 50 mg in 25 mL; individually boxed.

Store refrigerated, 2° to 8°C (36° to 46°F).

Protect from light. Retain in carton until time of use. Discard unused portion.

Adriamycin (DOXOrubicin HCI) Injection, USP is supplied in a sterile, multiple dose, flip-top vial, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strength:

NDC 0143-9546-01: 200 mg in 100 mL; individually boxed.

Store refrigerated, 2° to 8°C (36° to 46°F).

Protect from light. Retain in carton until contents are used.

Storage of vials of Adriamycin (DOXOrubicin HCl) Injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15º to 30ºC (59º to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Handling and Disposal

Handle and dispose of Adriamycin (DOXOrubicin HCl) Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs.1

Doxorubicin Breastfeeding Warnings

Peak milk concentrations of doxorubicin and its metabolite, doxorubicinol, averaged 128 and 111 ng/mL, respectively, 24 hours after a 70 mg/m2 IV dose was given to a 31 year old nursing woman. The milk to plasma concentration ratio at 24 hours was 4.43. Although doxorubicin concentrated into milk in this case, the absolute concentration of drug in the milk was only 0.24 mcg/mL. Although this amount appears negligible, experts consider the use of doxorubicin during breast-feeding to be contraindicated because of the known and suspected risks to the nursing infant.

Doxorubicin is excreted into and accumulates in human milk. Side effects, including immune suppression, carcinogenesis, neutropenia, and unknown effects on growth are possible in nursing infants. The American Academy of Pediatrics considers the use of doxorubicin to be contraindicated during breast-feeding.

Doxorubicin Levels and Effects while Breastfeeding

Summary of Use during Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, especially anthracyclines such as doxorubicin.[1] It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence; however, the high levels and persistence of doxorubicinol in milk make defining an appropriate abstinence interval difficult. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.[2] Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.

Drug Levels

Maternal Levels. Doxorubicin, doxorubicinol and two other metabolites were detected in milk after administration of 70 mg/sq m (90 mg) of doxorubicin intravenously. Peak milk levels of 128 mcg/L of doxorubicin and 111 mcg/L of its active metabolite doxorubicinol occurred 24 hours after the dose. Both drugs were detectable in milk for at least 72 hours after the dose. Other metabolites were also detected in milk at lower levels.[3][4] Using these data, the breastfed infant in this case would have received an estimated 2% of maternal weight-adjusted dosage if he had been allowed to nurse throughout the 72 hours after the dose.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

A study of adolescent males who had received chemotherapy for childhood malignancies found that having received doxorubicin was associated with elevated serum prolactin concentrations.[5]

A woman diagnosed with Hodgkin's lymphoma during the second trimester of pregnancy received 3 rounds of chemotherapy during the third trimester of pregnancy and resumed chemotherapy 4 weeks postpartum. Milk samples were collected 15 to 30 minutes before and after chemotherapy for 16 weeks after restarting. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg and dacarbazine 600 mg, all given over a 2-hour period every 2 weeks. The microbial population and metabolic profile of her milk were compared to those of 8 healthy women who were not receiving chemotherapy. The breastmilk microbial population in the patient was markedly different from that of the healthy women, with increases in Acinetobacter sp., Xanthomonadacae and Stenotrophomonas sp. and decreases in Bifidobacterium sp. and Eubacterium sp. Marked differences were also found among numerous chemical components in the breastmilk of the treated woman, most notably DHA and inositol were decreased.[2]

A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 62 women who received a doxorubicin-containing regimen, 39 had breastfeeding difficulties.[6]

References

1. Pistilli B, Bellettini G, Giovannetti E et al. Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: How should we counsel cancer patients about breastfeeding? Cancer Treat Rev. 2013;39:207-11. PMID: 23199900

2. Urbaniak C, McMillan A, Angelini M et al. Effect of chemotherapy on the microbiota and metabolome of human milk, a case report. Microbiome. 2014;2:24. PMID: 25061513

3. Egan PC, Costanza M, Dodion P et al. Secretion of doxorubicin (DOX) and cisplatin (DDP) into human milk. Proc ASCO. 1984;3:21. Abstract.

4. Egan PC, Costanza ME, Dodion P et al. Doxorubicin and cisplatin excretion into human milk. Cancer Treat Rep. 1985;69:1387-9. PMID: 4075315

5. Siimes MA, Ropponen P, Aalberg V et al. Prolactinemia in adolescent males surviving malignancies in childhood: impaired dating activity. J Adolesc Health. 1993;14:543-7. PMID: 8312290

6. Stopenski S, Aslam A, Zhang X et al. After chemotherapy treatment for maternal cancer during pregnancy, is breastfeeding possible? Breastfeed Med. 2017;12:91-7. PMID: 28170295

(web3)