Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

CYTOXAN (NDA-012142)

(CYCLOPHOSPHAMIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/05/2024 (SUPPL-116)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1), and Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for 4 months after completion of therapy [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Infertility [see Warnings and Precautions (5.8) and Use in Specific Populations (8.3, 8.4)]

6.1 Clinical Trials and Postmarketing Experience

Subsection title revised

Additions and/or revisions underlined:

The following adverse reactions associated with the use of cyclophosphamide were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.

The most common adverse reactions were neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

…

Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation, nausea, vomiting, diarrhea.

General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache, febrile neutropenia.

…

Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis, alopecia.

…

7 Drug Interactions

7.1 Effect of Other Drugs on Cyclophosphamide Exposure

Newly added subsection

Additions and/or revisions underlined:

Protease Inhibitors

Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites and may enhance the toxicities of cyclophosphamide, including higher incidence of infections, neutropenia, and mucositis. Monitor for increased toxicities in patients receiving protease inhibitors.

7.2 Drugs That Potentiate Cyclophosphamide Toxicities

Newly added subsection

Additions and/or revisions underlined:

Radiation therapy or drugs with similar toxicities to Cyclophosphamide for Injection can potentiate toxicities for cyclophosphamide. Monitor for increased toxicities in patients receiving radiation therapy or drugs known to cause:

Myelosuppression and/or immunosuppression [see Warnings and Precautions (5.1)]
Nephrotoxicity including hemorrhagic cystitis [see Warnings and Precautions (5.2)]

Cardiotoxicity [see Warnings and Precautions (5.3)]

Pulmonary toxicity [see Warnings and Precautions (5.4)]
Secondary malignancies [see Warnings and Precautions (5.5)]
Hepatotoxicity including liver necrosis and VOD [see Warnings and Precautions (5.6)]

7.3 Effect of Cyclophosphamide on Other Drugs

Newly added subsection

Additions and/or revisions underlined:

Metronidazole

Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Monitor for neurologic toxicities in patients receiving metronidazole.

Tamoxifen

Concomitant use of tamoxifen and a cyclophosphamide-containing chemotherapy regimen may increase the risk of thromboembolic complications. Monitor for signs and symptoms of thromboembolic events in patients receiving tamoxifen.

Coumarins

Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Monitor anticoagulant activity closely in patients receiving warfarin or other coumarins.

Cyclosporine

Concomitant administration of cyclophosphamide may decrease serum concentrations of cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. Monitor for signs and symptoms of graft-versus-host disease in patients receiving cyclosporine.

Depolarizing muscle relaxants

If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

Cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; please refer to label for complete information

Risk Summary

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data]. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2%-4% and miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Human Data

Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Animal Data

Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

8.2 Lactation

PLLR conversion; please refer to label for complete information

Risk summary

Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with Cyclophosphamide for Injection and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Cyclophosphamide for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide for Injection.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for up to 1 year after completion of therapy.

Males

Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide for Injection and for 4 months after completion of therapy [see Nonclinical Toxicology (13.1)].

Infertility

Females

Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.

Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see Nonclinical Toxicology (13.1)].

Males

Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)]. Monitor patients with severe hepatic impairment (total bilirubin > 3 x ULN and any aspartate aminotransferase (AST)) for reduced effectiveness of cyclophosphamide.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient of the following:

Myelosuppression, Immunosuppression and Infections

Inform patients of the possibility of myelosuppression, immunosuppression, and infections (sometimes fatal). Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever [see Warnings and Precautions (5.1)].

Urinary Tract and Renal Toxicity

Advise the patient to report urinary symptoms (patients should report if their urine has turned a pink or red color) and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2)].

Cardiotoxicity

Inform patients of the possibility of cardiotoxicity (which may be fatal).

Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.3)].

Pulmonary Toxicity

Warn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].

Secondary Malignancies

Inform patients that there is an increased risk of secondary malignancies with Cyclophosphamide for Injection [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity

Inform female patients of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]
Advise female patients of reproductive potential to use effective contraception during treatment and for up to 1 year after completion of therapy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after completion of therapy. [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise lactating women not to breastfeed during treatment and for 1 week after the last dose of Cyclophosphamide for Injection [see Use in Specific Populations (8.2)].
Infertility

Advise males and females of reproductive potential that Cyclophosphamide for Injection may impair fertility [see Warnings and Precautions (5.8) and Use in Specific Populations (8.3, 8.4)]

Common Adverse Reactions

Explain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the

ability to drive or use machines [see Adverse Reactions (6.1,6.2)].

Hydration and Important Administration Instructions

Advise the patients that during or immediately after the administration, adequate amounts of fluid are required to reduce the risk of urinary tract toxicity [see Dosage and Administration (2.1)].