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.

BORTEZOMIB (NDA-205004)

(BORTEZOMIB)

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

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09/20/2021 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Thrombotic Microangiopathy

(Newly added subsection)

Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in the postmarketing setting in patients who received bortezomib. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Bortezomib for Injection and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting Bortezomib for Injection. The safety of reinitiating Bortezomib for Injection therapy in patients previously experiencing TTP/HUS is not known.

5.11 Embryo-fetal Toxicity

(Additions and/or revisions underlined)

Based on the mechanism of action and findings in animals, Bortezomib for Injection can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Bortezomib for Injection and for 7 months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Bortezomib for Injection and for 4 months following treatment. If Bortezomib for Injection is used during pregnancy or if the patient becomes pregnant during Bortezomib for Injection treatment, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

5.2 Hypotension

(Additions and/or revisions underlined)

The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8% [see Adverse Reactions (6.1)]. These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated may be at increased risk of hypotension. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

5.3 Cardiac Toxicity

(Additions and/or revisions underlined)

Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction [see Adverse Reactions (6.1)]. Patients with risk factors for, or existing heart disease should be frequently monitored. In the relapsed multiple myeloma study of bortezomib versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was less than or equal to 1% for each individual reaction in the bortezomib group. In the dexamethasone group the incidence was less than or equal to 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

5.7 Thrombocytopenia/Neutropenia

(Additions and/or revisions underlined)

…

Table 7: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezomib versus Dexamethasone

…

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Thrombotic Microangiopathy [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Safety Experience

(Extensive changes; please refer to label)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified from the worldwide postmarketing experience with bortezomib. 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 disorders: Cardiac tamponade

Ear and labyrinth disorders: Deafness bilateral

Eye disorders: Optic neuropathy, blindness, chalazion/blepharitis

Gastrointestinal disorders: Ischemic colitis

Infections and infestations: Progressive multifocal leukoencephalopathy (PML), ophthalmic herpes, herpes meningoencephalitis

Nervous system disorders: Posterior reversible encephalopathy syndrome (PRES, formerly RPLS)

Respiratory, thoracic and mediastinal disorders: Acute diffuse infiltrative pulmonary disease

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute febrile neutrophilic dermatosis (Sweet's syndrome)

7 Drug Interactions

7.1 Effect of Other Drugs on Bortezomib

(Additions and/or revisions underlined)

Strong CYP3A4 Inducers

Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology (12.3)] which may decrease bortezomib efficacy. Avoid coadministration with strong CYP3A4 inducers.

Strong CYP3A4 Inhibitors

Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib [see Clinical Pharmacology (12.3)] which may increase the risk of bortezomib toxicities. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors.

7.2 Drugs Without Clinically Significant Interactions with Bortezomib

(Subsection title revised; Additions and/or revisions underlined)

No clinically significant drug interactions have been observed when bortezomib was coadministered with dexamethasone, omeprazole, or melphalan in combination with prednisone [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Based on its mechanism of action and findings in animals, Bortezomib for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Conduct pregnancy testing in females of reproductive potential prior to initiating Bortezomib for Injection treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Bortezomib for Injection and for 7 months after the last dose.

Males

Males with female partners of reproductive potential should use effective contraception during treatment with Bortezomib for Injection and for 4 months after the last dose.

Infertility

Based on the mechanism of action and findings in animals, Bortezomib for Injection may have an effect on either male or female fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

(Additions and/or revisions underlined)

Safety and effectiveness have not been established in pediatric patients.

The activity and safety of bortezomib in combination with intensive reinduction chemotherapy was evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%, 16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within 36 months of initial diagnosis in a single-arm multicenter, non-randomized cooperative group trial. An effective reinduction multiagent chemotherapy regimen was administered in three blocks. Block 1 included vincristine, prednisone, doxorubicin and pegaspargase; Block 2 included cyclophosphamide, etoposide and methotrexate; Block 3 included high dose cytosine arabinoside and asparaginase. Bortezomib was administered at a dose of 1.3 mg/m2 as a bolus intravenous injection on Days 1, 4, 8, and 11 of Block 1 and Days 1, 4, and 8 of Block 2. There were 140 patients with ALL or LL enrolled and evaluated for safety. The median age was ten years (range 1 to 26), 57% were male, 70% were white, 14% were black, 4% were Asian, 2% were American Indian/ Alaska Native, 1% were Pacific Islander.

The activity was evaluated in a pre-specified subset of the first 60 evaluable patients enrolled on the study with pre-B ALL less than or equal to 21 years and relapsed < 36 months from diagnosis. The complete remission (CR) rate at day 36 was compared to that in a historical control set of patients who had received the identical backbone therapy without bortezomib. There was no evidence that the addition of bortezomib had any impact on the CR rate.

No new safety concerns were observed when bortezomib was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without bortezomib.

The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.

8.6 Renal Impairment

(Additions and/or revisions underlined)

No starting dosage adjustment of Bortezomib for Injection is recommended for patients with renal impairment. In patients requiring dialysis, Bortezomib for Injection should be administered after the dialysis procedure [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

(Additions and/or revisions underlined)

No starting dosage adjustment of Bortezomib for Injection is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to 1x ULN and AST > ULN, or total bilirubin > 1 to 1.5x ULN and any AST). The exposure of bortezomib is increased in patients with moderate (total bilirubin greater than or equal to 1.5 to 3x ULN and any AST) and severe (total bilirubin > 3x ULN and any AST) hepatic impairment. Reduce the starting dose in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Discuss the following with patients prior to treatment with Bortezomib for Injection:

Peripheral Neuropathy: Advise patients to report the development or worsening of sensory and motor peripheral neuropathy to their healthcare provider [see Warnings and Precautions (5.1)].

Hypotension: Advise patients to drink adequate fluids to avoid dehydration and to report symptoms of hypotension to their healthcare provider [see Warnings and Precautions (5.2)].

Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps.

Cardiac Toxicity: Advise patients to report signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3)].

Pulmonary Toxicity: Advise patients to report symptoms of ARDS, pulmonary hypertension, pneumonitis, and pneumonia immediately to their healthcare provider [see Warnings and Precautions (5.4)].

Posterior Reversible Encephalopathy Syndrome (PRES): Advise patients to seek immediate medical attention for signs or symptoms of PRES [see Warnings and Precautions (5.5)].

Gastrointestinal Toxicity: Advise patients to report symptoms of gastrointestinal toxicity to their healthcare provider and to drink adequate fluids to avoid dehydration. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps [see Warnings and Precautions (5.6)].

Thrombocytopenia/Neutropenia: Advise patients to report signs or symptoms of bleeding or infection immediately to their healthcare provider [see Warnings and Precautions (5.7)].

Tumor Lysis Syndrome: Advise patients of the risk of tumor lysis syndrome and to drink adequate fluids to avoid dehydration [see Warnings and Precautions (5.8)].

Hepatic Toxicity: Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider

[see Warnings and Precautions (5.9)].

Thrombotic Microangiopathy: Advise patients to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur [see Warnings and Precautions (5.10)].

Ability to Drive or Operate Machinery or Impairment of Mental Ability: Bortezomib for Injection may cause fatigue, dizziness, syncope, orthostatic/postural hypotension. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Warnings and Precautions (5.2, 5.5)].

Embryo-fetal Toxicity: Advise females of the potential risk to the fetus and to use effective contraception during treatment with Bortezomib for Injection and for seven months following the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Bortezomib for Injection and for 4 months following the last dose. Instruct patients to report pregnancy to their physicians immediately if they or their female partner becomes pregnant during treatment or within seven months following last dose [see Warnings and Precautions (5.11)].

Lactation: Advise women not to breastfeeding while receiving Bortezomib for Injection and for 2 months after last dose [see Use in Specific Populations (8.2)].

Concomitant Medications: Advise patients to speak with their physicians about any other medication they are currently taking.

Diabetic Patients: Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level.

Dermal: Advise patients to contact their physicians if they experience rash, severe injection site reactions [see Dosage and Administration (2.7)], or skin pain. Discuss with patients the option for antiviral prophylaxis for herpes virus infection [see Adverse Reactions (6.1)].

Other: Instruct patients to contact their physicians if they develop an increase in blood pressure, bleeding, fever, constipation, or decreased appetite.