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.

CAMPATH (BLA-103948)

(ALEMTUZUMAB)

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

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04/26/2023 (SUPPL-5188)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Other Alemtuzumab Products

The following adverse reactions have been identified during postapproval use of another alemtuzumab product. 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.

Endocrine Disorders: Hypothyroidism, hyperthyroidism, and thyroiditis.

Nervous System Disorders: Autoimmune encephalitis.

08/18/2021 (SUPPL-5183)

Approved Drug Label (PDF)

6 Adverse Reactions

6.5 Postmarketing Experience

(Additions and/or revisions underlined)

Immune System Disorders: Autoimmune hepatitis, vasculitis, Guillain-Barré syndrome [see Warnings and Precautions (5.1)], hemophagocytic lymphohistiocytosis [see Warnings and Precautions (5.11)], sarcoidosis

10/22/2020 (SUPPL-5181)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Immunosuppression/Infections

(Additions underlined)

…

Epstein-Barr virus (EBV) infection, including severe and fatal EBV-associated hepatitis, has been reported in patients who received CAMPATH.

Monitor for sign and symptoms of EBV infections. Withhold CAMPATH for EBV reactivation or severe infection.

…

6 Adverse Reactions

6.3 Postmarketing Experience

(Additions underlined)

CAMPATH

…

Neoplasms: EBV-associated lymphoproliferative disorder.

…

06/29/2020 (SUPPL-5176)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

Infusion-Related Reactions: CAMPATH administration can result in serious, including fatal, infusion-related reactions. Carefully monitor patients during infusions and withhold CAMPATH for Grade 3 or 4 infusion-related reactions. Gradually escalate CAMPATH to the recommended dose at the initiation of therapy and after interruption of therapy for 7 or more days [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)].

Immunosuppression/Infections: Serious, including fatal, bacterial, viral, fungal, and protozoan infections can occur in patients receiving CAMPATH. Administer prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].

5 Warnings and Precautions

5.2 Infusion-Related Reactions

Addition of ‘-related’ to infusion throughout this subsection.

… Institute appropriate medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion-related reactions as needed [see Dosage and Administration (2.2)] …

6 Adverse Reactions

6.1 Clinical Trials Experiences

Infusion-Related Reactions

Addition of ‘-related’ to infusion throughout

6.2 Postmarketing Experience

Additions and/or revisions underlined:

CAMPATH.

General Disorders and Administration Site Conditions: Fatal infusion-related reactions

Cardiovascular Disorders: congestive heart failure, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents).

Cerebrovascular Disorders: Cervicocephalic arterial dissection, stroke, including hemorrhagic and ischemic stroke

Gastrointestinal Disorders: Acute acalculous cholecystitis

Immune System Disorders: Goodpasture’s syndrome, Graves’ disease, aplastic anemia, Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness, fatal transfusion associated graft versus host disease, hemophagocytic lymphohistiocytosis (HLH).

Infections: Epstein-Barr virus (EBV) including EBV-associated lymphoproliferative disorder, progressive multifocal leukoencephalopathy (PML), reactivation of latent viruses.

Metabolism and Nutrition Disorders: tumor lysis syndrome.

Nervous System Disorders: optic neuropathy.

Renal and Urinary Disorders: glomerular nephropathies.

Other Alemtuzumab Products

Endocrine Disorders: hypothyroidism, hyperthyroidism, and thyroiditis.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Cytopenias

Advise patients to report any signs or symptoms such as bleeding, easy bruising, petechiae or purpura, pallor, weakness or fatigue [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Infusion-Related Reactions

Advise patients of the signs and symptoms of infusion-related reactions and of the need to take premedications as prescribed [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Immunosuppression/Infections

… Advise patients that irradiation of blood products is required [see Warnings and Precautions (5.3)].

Immunization

Advise patients that they should not be immunized …

Newly added information at end of section:

Glomerular Nephropathies

Advise patients on signs and symptoms of glomerular nephropathies that may occur months to years after receiving CAMPATH [see Adverse Reactions (6.2)].

11/26/2019 (SUPPL-5171)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Immunization

(Additions and/or revisions underlined)

The safety of immunization with live viral vaccines following CAMPATH therapy has not been studied. Do not administer live viral vaccines to patients or infants born to patients receiving CAMPATH. The ability to generate an immune response to any vaccine following CAMPATH therapy has not been studied.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are discussed in greater detail in other sections of the label:

Cytopenias
Infusion Reactions

Immunosuppression/Infections

The most common adverse reactions with CAMPATH are: infusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnea), cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), infections (CMV viremia, CMV infection, other infections), gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia, anxiety). The most common serious adverse reactions are cytopenias, infusion reactions, and immunosuppression/infections.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on findings from animal studies, CAMPATH may cause fetal harm when administered to a pregnant woman.

Available data from published cohort studies in pregnant women are insufficient to establish a CAMPATH-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Alemtuzumab was embryolethal in pregnant huCD52 transgenic mice when administered during organogenesis. Human IgG antibodies are known to cross the placental barrier; therefore, CAMPATH may be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. Infants born to pregnant women treated with CAMPATH may be at increased risk of infection. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

Monoclonal antibodies are transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Consider the risks and benefits of administering live or live-attenuated vaccines to infants exposed to CAMPATH in utero.

Data

Animal Data

When alemtuzumab was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, no teratogenic effects were observed. However, there was an increase in embryolethality (increased postimplantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11-15. In a separate study in pregnant huCD52 transgenic mice, administration of alemtuzumab during organogenesis (GD 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, decreases in B-lymphocyte and T-lymphocyte populations were observed in the offspring at both doses tested.

In pregnant huCD52 transgenic mice administered alemtuzumab at doses of 3 or 10 mg/kg/day IV throughout gestation and lactation, there was an increase in pup deaths during the lactation period at 10 mg/kg. Decreases in T-lymphocyte and B-lymphocyte populations and in antibody response were observed in offspring at both doses tested.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of alemtuzumab in human milk, effects on milk production, or the breastfed child. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to alemtuzumab are unknown. Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice administered alemtuzumab. Maternal IgG is known to be present in human milk and when a drug is present in animal milk, it is likely that the drug will be present in human milk.

Because of the potential for serious adverse reactions from CAMPATH in a breastfed child, including reduced lymphocyte counts, advise lactating women not to breastfeed during treatment with CAMPATH and for at least 3 months following the last dose.

Data

Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice following intravenous administration of alemtuzumab at a dose of 10 mg/kg on postpartum days 8-12. Serum levels of alemtuzumab were similar in lactating mice and offspring on postpartum day 13 and were associated with evidence of pharmacological activity (decrease in lymphocyte counts) in the offspring.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating CAMPATH therapy.

Contraception

Females

CAMPATH may cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with CAMPATH and for at least 3 months after the last dose.

Infertility

Based on findings from animal studies, alemtuzumab may impair fertility in females and males of reproductive potential. The reversibility of the effect on fertility is unknown.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Cytopenias: Advise patients to report any signs or symptoms such as bleeding, easy bruising, petechiae or purpura, pallor, weakness or fatigue.

Infusion Reactions: Advise patients of the signs and symptoms of infusion reactions and of the need to take premedications as prescribed.

Infections: Advise patients to immediately report symptoms of infection (e.g. pyrexia) and to take prophylactic anti-infectives for PCP (trimethoprim/sulfamethoxazole DS or equivalent) and for herpes virus (famciclovir or equivalent) as prescribed.

Advise patients that irradiation of blood products is required.

Advise patients that they should not be immunized with live viral vaccines if they have recently been treated with CAMPATH. Advise females with infants exposed to CAMPATH in utero to inform the pediatrician of the exposure.

Embryo-fetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise female patients of reproductive potential to use effective contraception during treatment with CAMPATH and for 3 months after the final dose.

Lactation: Advise females not to breastfeed during treatment with CAMPATH and for 3 months after the final dose.

Infertility: Advise females and males of reproductive potential that CAMPATH may impair fertility.

07/31/2019 (SUPPL-5172)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Progressive Multifocal Leukoencephalopathy (PML)

(new subsection added)

Progressive multifocal leukoencephalopathy (PML) has occurred in a patient with MS treated with LEMTRADA. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML was diagnosed two months after the second course of LEMTRADA. The patient had previously received multiple MS therapies, but had not received other drugs for treatment of MS for more than one year. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was not taking any immunosuppressive or immunomodulatory medications concomitantly. Afterthe diagnosis of PML, the patient developed immune reconstitution inflammatory syndrome (IRIS). The patient’s condition improved, but mild residual neurologic sequelae remained at last follow-up.

At the first sign or symptom suggestive of PML, withhold LEMTRADA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

6 Adverse Reactions

(addition underlined)

The following serious adverse reactions are described below and elsewhere in the labeling:

…

Progressive Multifocal Leukoencephalopathy (PML)

…

6.5 Postmarketing Experience

(additions underlined)

…

Postmarketing Experience with LEMTRADA

…

Progressive multifocal leukoencephalopathy

…

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

MEDICATION GUIDE

(additions underlined)

…

What are the possible side effects of LEMTRADA?

LEMTRADA may cause serious side effects including:

…

Progressive multifocal leukoencephalopathy (PML). A rare brain infection that usually leads to death or severe disability has been reported with LEMTRADA. Symptoms of PML get worse over days to weeks. It is important that you call your doctor right away if you have any new or worsening medical problems that have lasted several days, including problems with:

Thinking
Eyesight
Strength
Balance
Weakness on 1 side of your body
Using your arms or legs

…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Progressive Multifocal Leukoencephalopathy

Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in a patient who received LEMTRADA. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

…

11/29/2018 (SUPPL-5167)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Addition of the following:

Cerebrovascular Disorders: Cervicocephalic arterial dissection, stroke, including hemorrhagic and ischemic stroke.

12/13/2017 (SUPPL-5159)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Infections

(additions underlined)

…

Listeria monocytogenes Infections

Listeria monocytogenes infections (e.g., meningitis, encephalitis, sepsis, and gastroenteritis), including fatal cases of Listeria meningoencephalitis, have occurred in LEMTRADA-treated patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months after the last LEMTRADA dose. The duration of increased risk for Listeria infection after LEMTRADA treatment is unknown.

Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry). Initiate these Listeria precautions prior to starting LEMTRADA treatment. The incubation period for Listeria monocytogenes ranges from 3 to 70 days. In most cases, signs and symptoms of invasive listeriosis start within 1 month of exposure to Listeria monocytogenes. Symptoms of Listeria infection include fever, chills, diarrhea, nausea, vomiting, headache, pains in joints and muscles, neck stiffness, difficulty walking, mental status changes, coma, and other neurologic changes. As is the case with many infections, treatment cannot always prevent mortality and morbidity related to Listeria infections. Therefore, advise patients to watch for symptoms of Listeria infection and seek prompt medical help if symptoms occur.

…

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

MEDICATION GUIDE

(additions underlined)

…

What are the possible side effects of LEMTRADA? LEMTRADA may cause serious side effects including:

…

serious infections. LEMTRADA may cause you to have serious infections while you receive and after receiving a treatment course. Serious infections may include:
…

listeria. People who receive LEMTRADA have an increased chance of getting an infection caused by the bacteria listeria, which can lead to significant complications or death. Avoid foods that may be a source for listeria (for example, deli meat, unpasteurized milk and cheese products, soft cheeses, or undercooked meat, seafood or poultry) or make sure that the food you eat which may contain listeria is heated well if you receive treatment with LEMTRADA.

…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Infections

…

Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes prior to receiving LEMTRADA and if they have had a recent course of LEMTRADA. The duration of increased risk for Listeria infection after LEMTRADA administration is not known. Inform patients that Listeria infection can lead to significant complications or death.

...

10/05/2017 (SUPPL-5157)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of alemtuzumab. 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.

Addition of the following:

Gastrointestinal: Acute acalculous cholecystitis