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.

DARZALEX (BLA-761036)

(DARATUMUMAB)

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

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11/01/2022 (SUPPL-45)

Approved Drug Label (PDF)

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

PATIENT INFORMATION

Additions and/or revisions underlined

DARZALEX may be used with other medicines called lenalidomide, thalidomide or pomalidomide. You should also read the Medication Guide that comes with lenalidomide, thalidomide or pomalidomide if you use DARZALEX with these medicines.

…

What are the possible side effects of DARZALEX?

DARZALEX may cause serious reactions, including:

…

… Get medical help right away if you get any of the following symptoms:

…

o eye pain

…

Decreases in blood cell counts. DARZALEX can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Decreases in blood cell counts are common with DARZALEX, but can be severe. Your healthcare provider will check your blood cell counts during treatment with DARZALEX. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.
…
The most common side effects of DARZALEX include:
…

decreased red blood cells

…

03/04/2022 (SUPPL-41)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

Additions and/or revisions underlined:

In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, 0.35% (6/1,713) of patients developed treatment-emergent anti-daratumumab antibodies. Of those, 4 patients tested positive for neutralizing antibodies.

01/21/2022 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion-Related Reactions

Additions underlined

…

Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension, and blurred vision [see Adverse Reactions (6.1)].

…

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Infusion-Related Reactions

Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions: itchy, runny or blocked nose; fever, chills, nausea, vomiting, throat irritation, cough, headache, dizziness or lightheadedness, tachycardia, chestdiscomfort, wheezing, shortness of breath or difficulty breathing, itching, and blurred vision [see Warnings and Precautions (5.1)].

…

Hereditary Fructose Intolerance (HFI)

DARZALEX contains sorbitol. Advise patients with HFI of the risks related to sorbitol [see Description (11)].

PATIENT INFORMATION

Additions underlined

Before you receive DARZALEX, tell your healthcare provider about all of your medical conditions, including if you:

…

have hereditary fructose intolerance (HFI). DARZALEX contains sorbitol. Sorbitol is a source of fructose. People with HFI cannot break down fructose, which may cause serious side effects.
…

What are the possible side effects of DARZALEX?
DARZALEX may cause serious reactions, including:
…

blurred vision

…

What are the ingredients in DARZALEX?

Active ingredient: daratumumab

Inactive ingredients: may include glacial acetic acid, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, mannitol, polysorbate 20, sodium acetate trihydrate, sodium chloride, sorbitol, and water for injection.

07/09/2021 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion-Related Reactions

(Additions and/or revisions underlined)

DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported [see Adverse Reactions (6.3)].

In clinical trials (monotherapy and combination: N=2,066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). The incidence of infusion modification due to reactions was 36%. Median durations of 16 mg/kg infusions for the Week 1, Week 2, and subsequent infusions were approximately 7, 4, and 3 hours respectively. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion-related reactions occurred up to 48 hours after infusion.

Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension [see Adverse Reactions (6.1)].

When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption for ASCT. Infusion-related reactions occurring at re- initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4:<1%) with those reported in previous studies at Week 2 or subsequent infusions.

1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 hours for Week 1-Day 1, 4.2 hours for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Newly added information)

Other Clinical Trials Experience

The following adverse reactions have been reported following administration of daratumumab and hyaluronidase for subcutaneous injection:

Nervous System disorders: Syncope

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Infusion-Related Reactions

Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions: itchy, runny or blocked nose; fever, chills, nausea, vomiting, throat irritation, cough, headache, dizziness or lightheadedness, tachycardia, chest discomfort, wheezing, shortness of breath or difficulty breathing, itching [see Warnings and Precautions (5.1)].

Patient Information

(Additions and/or revisions underlined)

DARZALEX is a prescription medicine used to treat adults with multiple myeloma:

• in combination with the medicines lenalidomide and dexamethasone in people with newly diagnosed multiple

myeloma who cannot receive a type of stem cell transplant that uses their own stem cells (autologous stem cell

transplant) and in people whose multiple myeloma has come back or did not respond to treatment who have

received at least one prior medicine to treat multiple myeloma.

• in combination with the medicines bortezomib, melphalan and prednisone, in people with newly diagnosed multiple

myeloma who cannot receive a type of stem cell transplant that uses their own stem cells (autologous stem cell

transplant).

• in combination with the medicines bortezomib, thalidomide, and dexamethasone in newly diagnosed people who

are eligible to receive a type of stem cell transplant that uses their own stem cells (autologous stem cell transplant).

• in combination with the medicines bortezomib and dexamethasone, in people who have received at least one prior

medicine to treat multiple myeloma.

• in combination with the medicines carfilzomib and dexamethasone, in people whose multiple myeloma has come

back or did not respond to treatment who have received one to three prior medicines to treat multiple myeloma.

o Females who are able to become pregnant should use an effective method of birth control (contraception)

during treatment and for 3 months after your last dose of DARZALEX. Talk to your healthcare provider about

birth control methods that you can use during this time.

You should not breastfeed during treatment with DARZALEX. Talk to your healthcare provider about the best way to feed your

baby during treatment with DARZALEX.

DARZALEX may cause serious reactions, including:

• Infusion-related reactions. Infusion-related reactions are common with DARZALEX. Serious allergic reactions

and reactions due to release of certain substances by your body (systemic) that can lead to death, can happen with

DARZALEX.

DARZALEX if you have infusion-related reactions. Get medical help right away if you get any of the following

symptoms:

• shortness of breath or trouble breathing

• dizziness or lightheadedness

(hypotension)

• cough

• wheezing

• heart beating faster than usual

• low oxygen in the blood

(hypoxia)

• throat tightness or irritation

• runny or stuffy nose

• headache

• itching

• high blood pressure

• nausea

• vomiting

• chills

• fever

• chest discomfort

03/12/2021 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions underlined

…

Infections: Cytomegalovirus, Listeriosis

08/20/2020 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes with new information added for this subsection; please refer to label for complete information.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 2,459 patients who received DARZALEX at the recommended dose, 38% were 65 to 74 years of age, and 15% were 75 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. The incidence of serious adverse reactions was higher in older than in younger patients [see Adverse Reactions (6.1)]. Among patients with relapsed and refractory multiple myeloma (n=1,213), the serious adverse reactions that occurred more frequently in patients 65 years and older were pneumonia and sepsis. Within the DKd group in CANDOR, fatal adverse reactions occurred in 14% of patients 65 years and older compared to 6% of patients less than 65 years. Among patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (n=710), the serious adverse reaction that occurred more frequently in patients 75 years and older was pneumonia.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

What is DARZALEX?

DARZALEX is a prescription medicine used to treat adults with multiple myeloma:

in combination with the medicines carfilzomib and dexamethasone, in people who have received one to three prior medicines to treat multiple myeloma.

06/29/2020 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Infusion-Related Reactions

DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. In clinical trials (monotherapy and combination treatments: N=2,066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 72.8 hours). The incidence of infusion modification due to reactions was 36%. Median durations of 16 mg/kg infusions for the Week 1, Week 2, and subsequent infusions were approximately 7, 4, and 3 hours respectively. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion-related reactions occurred up to 48 hours after infusion.

When DARZALEX dosing was interrupted in the setting of ASCT (Study CASSIOPEIA) for a median of 3.75 months (range: 2.4; 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption for ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4:<1%) with those reported in previous studies at Week 2 or subsequent infusions.

In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 h for Week 1-Day 1, 4.2 h for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics and corticosteroids. Frequently monitor patients during the entire infusion [see Dosage and Administration (2.3)]. Interrupt DARZALEX infusion for …

… For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion [see Dosage and Administration (2.4)].

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids …

Additions and/or revisions underlined:

5.3 Neutropenia

Additions and/or revisions underlined:

… Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX until recovery of neutrophils.

5.4 Thrombocytopenia

Additions and/or revisions underlined:

Newly added subsection:

5.6 Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX can cause fetal harm when administered to a pregnant woman. DARZALEX may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

6 Adverse Reactions

Throughout this section '-related' follows infusion.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

DARZALEX can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted …

… 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. T

The combination of DARZALEX and lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women, because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Lenalidomide, pomalidomide, and thalidomide are only available through a REMS program. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX may cause depletion of fetal CD38 positive immune cells and decreased bone density …

Data

Animal Data

Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in regulating humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There is no data on the presence of daratumumab in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin G is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX is administered with lenalidomide, pomalidomide, or thalidomide, advise women not to breastfeed during treatment with DARZALEX. Refer to lenalidomide, pomalidomide, or thalidomide prescribing information for additional information.

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

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

Pregnancy Testing

With the combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide, refer to the lenalidomide, pomalidomide, or thalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.

Contraception

Advise females of reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose. Additionally, refer to the lenalidomide, pomalidomide, or thalidomide labeling for additional recommendations for contraception.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Infusion-Related Reactions

Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions …

… Interference with Laboratory Tests

Advise patients to inform their healthcare providers, including personnel at blood transfusion centers that they are taking DARZALEX, in the event of a planned transfusion [see Warnings and Precautions (5.2)].

Newly added information:

Embryo-Fetal Toxicity

Advise pregnant women of the potential hazard to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)]

Advise females of reproductive potential to avoid becoming pregnant during treatment with DARZALEX and for at least 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

Advise patients that lenalidomide, pomalidomide, or thalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide, pomalidomide, and thalidomide are only available through a REMS program [see Use in Specific Populations (8.1, 8.3)]

PATIENT INFORMATION

Additions and/or revisions underlined:

Before you receive DARZALEX, tell your healthcare provider about all of your medical conditions, including if you:

are pregnant or plan to become pregnant. DARZALEX may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with DARZALEX.
- Females who are able to become pregnant should use an effective method of birth control (contraception) during treatment and for at least 3 months after your final dose of DARZALEX. Talk to your healthcare provider about birth control methods that you can use during this time.
- Before starting DARZALEX in combination with lenalidomide, pomalidomide, or thalidomide, females and males must agree to the instructions in the lenalidomide, pomalidomide, or thalidomide REMS program.
  - The lenalidomide, pomalidomide, and thalidomide REMS has more information about effective methods of birth control, pregnancy testing, and blood donation for females who can become pregnant.
  - For males who have female partners who can become pregnant, there is information in the lenalidomide, pomalidomide, and thalidomide REMS about sperm donation and how lenalidomide, pomalidomide, and thalidomide can pass into human semen.

What are the possible side effects of DARZALEX?

DARZALEX may cause serious reactions, including:

Infusion-related reactions. Infusion-related reactions are common …

04/17/2020 (SUPPL-27)

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 DARZALEX. 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.

Immune System disorders: Anaphylactic reaction

Gastrointestinal disorders: Pancreatitis

09/26/2019 (SUPPL-24)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive revisions; please refer to labeling for complete information)

6.2 Immunogenicity

(additions and/or revisions are underlined)

As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to daratumumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 of the 1,050 evaluable combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti- daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.

8 Use in Specific Populations

8.5 Geriatric Use

(additions and/or revisions are underlined)

Of the 2,066 patients that received DARZALEX at the recommended dose, 37% were 65 to 75 years of age, and 16% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

07/16/2019 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Hepatitis B Virus (HBV) Reactivation

Hepatitis B virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Hepatitis B virus (HBV) reactivation:

Advise patients to inform healthcare providers if they have ever had or might have a hepatitis B infection and that DARZALEX could cause hepatitis B virus to become active again.

PATIENT INFORMATION

(additions underlined)

…

Before you receive DARZALEX, tell your healthcare provider about all of your medical conditions, including if you:

…

have ever had or might now have a hepatitis B infection as DARZALEX could cause hepatitis B virus to become active again. Your healthcare provider will check you for signs of this infection before, during and for some time after treatment with DARZALEX. Tell your healthcare provider right away if you get worsening tiredness or yellowing of your skin or white part of your eyes.

…

06/27/2019 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and revisions, please refer to label for more information)

8 Use in Specific Populations

8.5 Geriatric Use

(revisions underlined)

Of the 1530 patients that received DARZALEX at the recommended dose, 48% were 65 to 75 years of age, and 22% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients

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

PATIENT INFORMATION

(additions underlined)

What is DARZALEX?

DARZALEX is a prescription medicine used to treat adult patients with multiple myeloma:

In combination with the medicines lenalidomide and dexamethasone in people with newly diagnosed multiple myeloma who cannot receive a type of stem cell transplant that uses their own stem cells (autologous stem cell transplant) and in people who have received at least one prior medicine to treat multiple myeloma

…

02/08/2019 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Infusion Reactions

…

In EQUULEUS, patients receiving daratumumab combination treatment (n=97) were administered the first 16 mg/kg daratumumab dose at Week 1 split over two days i.e. 8 mg/kg on Day 1 and Day 2 respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions. The median time to onset of a reaction was 1.8 hours (range: 0.1 to 5.4 hours). The incidence of infusion interruptions due to reactions was 30%. Median durations of infusions were 4.2 h for Week 1-Day 1, 4.2 h for Week 1-Day 2, and 3.4 hours for the subsequent infusions.

…

06/18/2018 (SUPPL-14)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following:

DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylactic reactions) to daratumumab or any of the components of the formulation.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Infusion Reactions

DARZALEX can cause severe and/or serious infusion reactions including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were Grade 1-2 …

… Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions …

6 Adverse Reactions

Newly added subsection:

6.3 Postmarketing Experience

Immune System disorders: Anaphylactic reaction

7 Drug Interactions

7.1 Effects of Daratumumab on Laboratory Tests

Interference with Serum Protein Electrophoresis and Immunofixation Tests

Additions and/or revisions underlined:

… In patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.

05/07/2018 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Adverse Reactions in Clinical Trials

Table 7: Adverse reactions reported in greater than or equal to 10% of patients and with at least a 5% greater frequency in the DRd arm in POLLUX

Laboratory abnormalities worsening during treatment from baseline listed in Table 8.

Table 8: Treatment-emergent hematology laboratory abnormalities in POLLUX

In table column reading All Grades now reads Any Grades

Combination Treatment with Bortezomib

Adverse reactions described in Table 9 reflect exposure to DARZALEX (DVd arm) … for the bortezomib group (Vd) in CASTOR …

Table 9: Adverse reactions reported in greater than or equal to 10% of patients and with at least a 5% greater frequency in the DVd arm CASTOR

Laboratory abnormalities worsening during treatment are listed in Table 10.

Table 10: Treatment-emergent hematology laboratory abnormalities in CASTOR

Combination Treatment with Pomalidomide

… median treatment duration of 6 months (range: 0.03 to 16.9 months) in EQUULEUS …

Table 11: Adverse reactions with incidence greater than or equal to 10% reported in EQUULEUS

Laboratory abnormalities worsening during treatment are listed in Table 12.

Table 12: Treatment-emergent hematology laboratory abnormalities in EQUULEUS

Monotherapy

… Adverse reactions occurring in at least 10% of patients are presented in Table 13. Table 14 describes Grade 3–4 laboratory abnormalities …

Table 13: Adverse reactions with incidence greater than or equal to 10% in patients with multiple myeloma treated with DARZALEX 16 mg/kg

Table 14: Treatment emergent Grade 3-4 laboratory abnormalities (greater than or equal to 10%)

Infusion Reactions

In clinical trials (monotherapy and combination treatments; N=1166) the incidence of any grade infusion reactions was 40% with the first infusion of DARZALEX, 2% with the second infusion, and 4% with subsequent infusions. Less than 1% of patients had a Grade 3 infusion reaction with second or subsequent infusions. Grade 4 infusion reactions were reported in 2/1166 (0.2%) of patients.

… The incidence of infusion modification due to reactions was 37%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7.0, 4.3, and 3.4 hours respectively … Other adverse infusion reactions included nasal congestion …

Herpes Zoster Virus Reactivation

DARZALEX replaces DPd (Study 5) in this paragraph.

Infections

… background therapies (DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; D-VMP:23%, VMP:15%; DPd: 28 … 4% versus 3% of patients in the DVd and Vd groups respectively, 1% each in the D-VMP and VMP groups respectively, and in 5% of patients receiving DPd. Fatal infections were generally balanced between the DARZALEX containing regimens and active control arms (less than 2) in the controlled studies and were primarily due to pneumonia and sepsis.

Additions and/or revisions underlined:

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 1166 patients with multiple myeloma including 872 patients from three Phase 3 active-controlled trials who received DARZALEX in combination with either lenalidomide and dexamethasone (DRd, n=283; POLLUX), bortezomib and dexamethasone (DVd, n=243; CASTOR) or bortezomib, melphalan and prednisone (D-VMP, n=346; ALCYONE), and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide and dexamethasone (DPd, n=103; EQUULEUS), in combination with lenalidomide and dexamethasone (n=35), or as monotherapy (n=156).

Addition of the following:

Newly Diagnosed Multiple Myeloma

Combination Treatment with Bortezomib, Melphalan and Prednisone

Adverse reactions described in Table 5 reflect exposure to DARZALEX (D-VMP arm) for a median treatment duration of 14.7 months (range: 0 to 25.8 months) and median treatment duration of 12 months (range: 0.1 to 14.9 months) for the VMP group in ALCYONE. The most frequent adverse reactions (greater than or equal to 20% with at least 5% greater frequency in the D-VMP arm) were infusion reactions, upper respiratory tract infection and edema peripheral. Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).

Table 5: Adverse reactions reported in greater than or equal to 10% of patients and with at least a 5% greater frequency in the D-VMP arm in ALCYONE Newly added table; please refer to label for complete information.

Laboratory abnormalities worsening during treatment from baseline listed in Table 6.

Table 6: Treatment-emergent hematology laboratory abnormalities in ALCYONE Newly added table; please refer to label for complete information.

Additions and/or revisions underlined:

Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide

… and median treatment duration of 12.3 months (range: 0.2 to 20.1 months) for the lenalidomide group (Rd) in POLLUX.

6.2 Immunogenicity

Additions and/or revisions underlined:

… there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to daratumumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading … and 2 of the 411 combination therapy patients …

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

… The estimated 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 …

8.2 Lactation

Child replaces infant in this subsection.

8.5 Geriatric Use

Additions and/or revisions underlined:

… Of the 1166 patients that received DARZALEX at the recommended dose, 46% were 65 to 75 years of age, and 15% were 75 years of age or older …

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

PATIENT INFORMATION

Additions and/or revisions underlined:

What is DARZALEX?

DARZALEX is a prescription medicine used to treat multiple myeloma:

in combination with the medicines bortezomib, melphalan and prednisone, in people with newly diagnosed with multiple myeloma who cannot receive a type of stem cell transplant that uses their own stem cells (autologous stem cell transplant).

How will I receive DARZALEX?

DARZALEX will be given to you by your healthcare provider by intravenous (IV) infusion into your vein.

What are the possible side effects of DARZALEX? DARZALEX may cause serious reactions, including:

Infusion reactions … Get medical help right away if you get any of the following symptoms (replaces Tell your Healthcare provider right away if you get …)
Decreases in blood cell counts. DARZALEX can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Your healthcare provider will check your blood cell counts during treatment with DARZALEX …

The most common side effects of DARZALEX include:

Addition of the following:

Trouble sleeping
Joint pain
Vomiting
Chills
Dizziness

06/19/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Adverse Reactions in Clinical Trials

(Additions and/or revisions are underlined)

…

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 820 patients with multiple myeloma including 526 patients from two Phase 3 active-controlled trials who received DARZALEX in combination with either lenalidomide (DRd, n=283; Study 3) or bortezomib (DVd, n=243; Study 4) and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide (DPd, n=103; Study 5), in combination with lenalidomide (n=35), or as monotherapy (n=156)…

Combination Treatment with Pomalidomide

Adverse reactions described in Table 8 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months) in Study 5. The most frequent adverse reactions (>20%) were infusion reactions, diarrhea, constipation, nausea, vomiting, fatigue, pyrexia, upper respiratory tract infection, muscle spasms, back pain, arthralgia, dizziness, insomnia, cough and dyspnea. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in greater than or equal to 5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients.

Table 8: Adverse reactions with incidence Greater than or Equal to 10% reported in Study 5 (Table has been added; please refer to label)

Laboratory abnormalities worsening during treatment are listed in Table 9.

Table 9: Treatment-emergent hematology laboratory abnormalities in Study 5 (Table has been added; please refer to label)

Monotherapy

…

Adverse reactions occurring in at least 10% of patients are presented in Table 10. Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ?10%.

Infusion Reactions

In clinical trials (monotherapy and combination treatments; N=820) the incidence of any grade infusion reactions was 46% with the first infusion of DARZALEX, 2% with the second infusion, and 3% with subsequent infusions…

The median time to onset of a reaction was 1.4 hours (range: 0.02 to 72.8 hours). The incidence of infusion modification due to reactions was 42%...

…Other adverse infusion reactions (any Grade, greater than or equal to 5%) were nasal congestion, cough, chills, throat irritation, vomiting and nausea.

Herpes Zoster Virus Reactivation

…In the randomized controlled combination therapy studies, herpes zoster was reported in 2% each in the DRd and Rd groups respectively (Study 3), in 5% versus 3% in the DVd and Vd groups respectively (Study 4) and in 2% of patients receiving DPd (Study 5).

Infections

In patients receiving DARZALEX combination therapy, Grade 3 or 4 infections were reported with DARZALEX combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 28%, Rd: 23%; DPd: 28%).

…Discontinuations from treatment were reported in 3% versus 2% of patients in the DRd and Rd groups respectively, 4% versus 3% of patients in the DVd and Vd groups respectively and in 5% of patients receiving DPd…

6.2 Immunogenicity

(Additions and/or revisions are underlined)

…In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 2 (0.7%) of the 298 combination therapy patients, tested positive for anti-daratumumab antibodies. One patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

…Of 664 patients that received DARZALEX with various combination therapies, 41% were 65 to 75 years of age, and 9% were 75 years of age or older…

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

PATIENT INFORMATION

(Additions and/or revisions are underlined)

What is DARZALEX?

DARZALEX is a prescription medicine used to treat multiple myeloma:

In combination with the medicines pomalidomide and dexamethasone in people who have received at least two prior medicines to treat multiple myeloma, including lenalidomide and a proteasome inhibitor.

11/21/2016 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion Reaction (addition underlined)

Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

5.3 Neutropenia (Newly added, New subsection added)

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.

5.4 Thrombocytopenia (Newly added, New subsection added)

DARZALEX may increase thrombocytopenia induced by background therapy.

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.

6 Adverse Reactions

6.2 Immunogenicity (addition underlined)

As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or as combination therapies, none of the 111 evaluable monotherapy patients, and 1 (0.4%) of the 234 combination therapy patients, tested positive for anti-daratumumab antibodies. This patient administered DARZALEX as combination therapy, developed transient neutralizing antibodies against daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab; therefore, the incidence of antibody development might not have been reliably determined.

8 Use in Specific Populations

8.5 Geriatric Use (addition underlined)

Of the 156 patients that received DARZALEX monotherapy at the recommended dose, 45% were 65 years of age or older, and 10% were 75 years of age or older. Of 561 patients that received DARZALEX with various combination therapies, 40% were 65 to 75 years of age, and9% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

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

17 PATIENT COUNSELING INFORMATION (addition underlined)

Neutropenia

• Advise patients that if they have a fever, they should contact their healthcare professional.

Thrombocytopenia

• Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding

PATIENT INFORMATION (addition underlined)

DARZALEX is a prescription medicine used to treat multiple myeloma:

• In combination with the medicines lenalidomide and dexamethasone, or bortezomib and dexamethasone, in people who have received at least one prior medicine to treat multiple myeloma.

• Alone in people who have received at least three prior medicines to treat multiple myeloma, including a proteasome inhibitor and an immunomodulatory agent, or did not respond to a proteasome inhibitor and immunomodulatory agent.

How will I receive DARZALEX?

• DARZALEX may be given alone or together with other medicines used to treat multiple myeloma.

• DARZALEX will be given to you by intravenous (IV) infusion into your vein.

• Your healthcare provider will decide the time between doses as well as how many treatments you will receive.

• Your healthcare provider will give you medicines before each dose of DARZALEX and on the first day after each dose of DARZALEX to help reduce the risk of infusion reactions.

DARZALEX may cause serious reactions, including:

• Infusion reactions. Infusion reactions are common with DARZALEX and can be severe. Your healthcare providermay temporarily stop your infusion or completely stop treatment with DARZALEX if you have infusion reactions. Tell your healthcare provider right away if you get any of the following symptoms:

• shortness of breath or trouble breathing

• dizziness or lightheadedness (hypotension)

• cough

• wheezing

• throat tightness

• runny or stuffy nose

• headache

• itching

• nausea

• vomiting

• chills

• fever

• Decreases in blood cell counts. DARZALEX can decrease white blood cell counts which help fight infections and blood cells called platelets which help to clot blood. Tell your healthcare provider if you develop fever or have signs of bruising or bleeding.

The most common side effects of DARZALEX include:

• diarrhea

• shortness of breath

• muscle spasms

• nerve damage causing tingling, numbness or pain

• swollen hands ankles or feet

11/21/2016 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Infusion Reaction (addition underlined)

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

5.3 Neutropenia (Newly added, New subsection added)

DARZALEX may increase neutropenia induced by background therapy.

5.4 Thrombocytopenia (Newly added, New subsection added)

DARZALEX may increase thrombocytopenia induced by background therapy.

6 Adverse Reactions

(addition underlined)

• Neutropenia

• Thrombocytopenia

6.1 Adverse Reactions in Clinical Trials

(Extensive changes; please refer to label)

6.2 Immunogenicity (addition underlined)

8 Use in Specific Populations

8.5 Geriatric Use (addition underlined)

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

17 PATIENT COUNCELING INFORMATION (addition underlined)

Neutropenia

• Advise patients that if they have a fever, they should contact their healthcare professional.

Thrombocytopenia

• Advise patients to inform their healthcare professional if they notice signs of bruising or bleeding

PATIENT INFORMATION (addition underlined)

DARZALEX is a prescription medicine used to treat multiple myeloma:

• In combination with the medicines lenalidomide and dexamethasone, or bortezomib and dexamethasone, in people who have received at least one prior medicine to treat multiple myeloma.

How will I receive DARZALEX?

• DARZALEX may be given alone or together with other medicines used to treat multiple myeloma.

• DARZALEX will be given to you by intravenous (IV) infusion into your vein.

• Your healthcare provider will decide the time between doses as well as how many treatments you will receive.

• Your healthcare provider will give you medicines before each dose of DARZALEX and on the first day after each dose of DARZALEX to help reduce the risk of infusion reactions.

DARZALEX may cause serious reactions, including:

• shortness of breath or trouble breathing

• dizziness or lightheadedness (hypotension)

• cough

• wheezing

• throat tightness

• runny or stuffy nose

• headache

• itching

• nausea

• vomiting

• chills

• fever

The most common side effects of DARZALEX include:

• diarrhea

• shortness of breath

• muscle spasms

• nerve damage causing tingling, numbness or pain

• swollen hands ankles or feet