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.

ORBACTIV (NDA-206334)

(ORITAVANCIN DIPHOSPHATE)

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

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07/23/2021 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

4.2 Hypersensitivity

Additions and/or revisions underlined:

ORBACTIV is contraindicated in patients with known hypersensitivity to oritavancin products.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Hypersensitivity

Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of oritavancin products, including ORBACTIV …

5.3 Infusion Related Reactions

ORBACTIV is administered as a single dose by intravenous infusion, using a total infusion time of 3 hours to minimize the risk of infusion-related reactions. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including oritavancin products (e.g. ORBACTIV) …

5.4 Clostridioides difficile-associated Diarrhea

…

6 Adverse Reactions

Additions and/or revisions underlined:

Clostridioides difficile-associated Diarrhea [see Warnings and Precautions (5.4)]

Newly added subsection:

6.2 Immunogenicity

There is potential for immunogenicity following administration of oritavancin products, including ORBACTIV. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Because several factors in an assay may influence the observed incidence of antibody positivity, comparison of the incidence of antibodies to oritavancin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Positive indirect and direct antiglobulin tests (IAT/DAT) were noted with the administration of ORBACTIV and KIMYRSA (hereinafter referred to as another oritavancin product) in studies with healthy subjects and patients with ABSSSI. In a randomized, open-label, multi-center ABSSSI study, positive antiglobulin tests were reported in 9.6% (5/52) of subjects who received ORBACTIV and 2% (1/50) of subjects who received another oritavancin product. Oritavancin- dependent RBC antibodies were detected when tested in the presence of drug for three subjects in the ORBACTIV group.

In a multiple dose study with ORBACTIV in healthy volunteers, 90% (9/10) of subjects had a positive IAT 14 days after the second infusion.

In a healthy volunteer study, 66% (22/32) of subjects receiving another oritavancin product had a positive IAT 15 days after receiving dosing and one subject had a positive DAT at 8 days after dosing.

There were no reports of hemolysis in subjects who had positive IAT/DAT. If hemolytic anemia develops following treatment with ORBACTIV provide appropriate care. Positive IAT may interfere with cross-matching before blood transfusion [see Drug Interactions (7.2)].

7 Drug Interactions

7.2 Drug-Laboratory Test Interactions

Additions and/or revisions underlined:

Prolongation of Certain Laboratory Coagulation Tests

ORBACTIV may artificially prolong certain laboratory coagulation tests (see Table 2) by binding to and preventing the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests [see Contraindications (4.1) and Warnings and Precautions (5.1, 5.5)] …

Table 2: Coagulation Tests Affected and Unaffected by ORBACTIV

Positive Indirect and Direct Antiglobulin Tests (IAT/DAT)

Positive IAT/DAT were noted with administration of oritavancin products, including ORBACTIV, in studies with healthy volunteers and patients with ABSSSI. Positive IAT may interfere with cross-matching before blood transfusion [see Adverse Reactions (6.2)].

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

PATIENT COUNSELING INFORMATION

Allergic Reactions

Additions and/or revisions underlined:

… They should inform their healthcare provider about any previous hypersensitivity reactions to oritavancin products, other glycopeptides (vancomycin, telavancin, or dalbavancin) or other allergens.

12/11/2019 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hypersensitivity

(addition underlined)

Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of ORBACTIV.

…

5.3 Infusion Related Reactions

(additions underlined)

…Infusion reactions characterized by chest pain, back pain, chills and tremor have been observed with the use of ORBACTIV, including after the administration of more than one dose of ORBACTIV during a single course of therapy. Stopping or slowing the infusion may result in cessation of these reactions. The safety and effectiveness of more than one dose of ORBACTIV during a single course of therapy have not been established.

5.7 Development of Drug Resistant Bacteria

(addition underlined)

Prescribing ORBACTIV in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no available data on ORBACTIV use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no effects on embryo-fetal development or survival were observed in pregnant rats or rabbits treated at the highest doses throughout organogenesis with intravenous oritavancin, at doses equivalent to 25% of the single clinical dose of 1200 mg (see Data).

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, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oritavancin at the highest doses administered throughout organogenesis, 30 mg/kg/day (gestation days 6-17) and 15 mg/kg/day (gestation days 7-19), respectively. Those doses would be equivalent to a human dose of 300 mg, or 25% of the single clinical dose of 1200 mg. Higher doses were not evaluated in nonclinical developmental and reproductive toxicology studies.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of oritavancin in human milk, the effects on the breastfed- child, or the effects on milk production. ORBACTIV is present in the breast milk of rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORBACTIV and any potential adverse effects on the breast-fed child from ORBACTIV or from the underlying maternal condition.

Data

Following a single intravenous infusion in lactating rats, radio-labeled [14C]-oritavancin was excreted in milk and absorbed by nursing pups.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Development of Antibacterial Resistance

Patients should be counseled that antibacterial drugs including ORBACTIV should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ORBACTIV is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ORBACTIV or other antibacterial drugs in the future.

03/20/2018 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Infusion Related Reactions

(additions underlined)

ORBACTIV is administered via intravenous infusion, using a total infusion time of 3 hours to minimize the risk of infusion-related reactions. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including ORBACTIV, that resemble “Red- man Syndrome”, including flushing of the upper body, urticaria, pruritus and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.

10/17/2016 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Potential Risk of Bleeding with Concomitant Use of Warfarin (subsection added)

ORBACTIV has been shown to artificially prolong prothrombin time (PT) and international normalized ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an ORBACTIV dose.

Patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin.

7 Drug Interactions

7.1 Effect of ORBACTIV on CYP Substrates (addition underlined)

A screening drug-drug interaction study indicated that ORBACTIV is a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms. A drug-drug interaction study that assessed the interaction potential of a single 1200 mg dose of ORBACTIV on the pharmacokinetics of S-warfarin (CYP2C9 probe substrate) showed no effect of ORBACTIV on S-warfarin Cmax or AUC.

Avoid administering ORBACTIV concomitantly with drugs with a narrow therapeutic window that are predominantly metabolized by one of the affected CYP450 enzymes, as co- administration may increase or decrease concentrations of the narrow therapeutic range drug. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given ORBACTIV while on a potentially affected compound (e.g. patients should be monitored for bleeding if concomitantly receiving ORBACTIV and warfarin).

01/20/2016 (SUPPL-2)

Approved Drug Label (PDF)

4 Contraindications

Intravenous Unfractionated Heparin Sodium

Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after Orbactiv administration because the activated partial thromboplastin time (aPTT) test results may remain falsely elevated for up to 120 hours (5 days) after Orbactiv administration

5 Warnings and Precautions

Potential Risk of Bleeding with Concomitant Use of Warfarin

… Orbactiv has been shown to artificially prolong prothrombin time (PT) and international normalized ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an Orbactiv dose

Coagulation Test Interference

Orbactiv has been shown to artificially prolong aPTT for up to 120 hours, PT and INR for up to 12 hours, and activated clotting time (ACT) for up to 24 hours following administration of a single 1200 mg dose by binding to and preventing action of the phospholipid reagents commonly used in laboratory coagulation tests. Orbactiv has also been shown to elevate D-dimer concentrations up to 72 hours after Orbactiv administration. For patients who require aPTT monitoring within 120 hours of Orbactiv dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered. Orbactiv has no effect on the coagulation system in vivo.