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.

FORTEO (NDA-021318)

(TERIPARATIDE RECOMBINANT HUMAN)

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

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11/16/2020 (SUPPL-54)

Approved Drug Label (PDF)

Boxed Warning

Removal of Osteosarcoma Boxed Warning

4 Contraindications

Additions and/or revisions underlined:

FORTEO is contraindicated in patients with hypersensitivity to teriparatide or to any of its excipients. Hypersensitivity reactions have included angioedema and anaphylaxis [see Adverse Reactions (6.3)].

5 Warnings and Precautions

5.1 Osteosarcoma

Additions and/or revisions underlined:

An increase in the incidence of osteosarcoma (a malignant bone tumor) was observed in male and female rats treated with teriparatide. Osteosarcoma has been reported in patients treated with FORTEO in the post marketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of FORTEO use [see Dosage and Administration (2.3), Adverse Reactions (6.3), and Nonclinical Toxicology (13.1)].

Avoid FORTEO use in patients with (these patients are at increased baseline risk of osteosarcoma):

Open epiphyses (pediatric and young adult patients) (FORTEO is not approved in pediatric patients [see Use in Specific Populations (8.4)].

Metabolic bone diseases other than osteoporosis, including Paget’s disease of the bone.
Bone metastases or a history of skeletal malignancies.
Prior external beam or implant radiation therapy involving the skeleton.

5.2 Hypercalcemia and Cutaneous Calcification

Additions and/or revisions underlined:

Hypercalcemia

FORTEO has not been studied in patients with pre-existing hypercalcemia. FORTEO may cause hypercalcemia and may exacerbate hypercalcemia in patients with pre-existing hypercalcemia [see Adverse Reactions (6.1, 6.3)]. Avoid FORTEO in patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism.

Risk of Cutaneous Calcification Including Calciphylaxis

Serious reports of calciphylaxis and worsening of previously stable cutaneous calcification have been reported in the post- marketing setting in patients taking FORTEO. Risk factors for development of calciphylaxis include underlying auto- immune disease, kidney failure, and concomitant warfarin or systemic corticosteroid use. Discontinue FORTEO in patients who develop calciphylaxis or worsening of previously stable cutaneous calcification.

5.3 Risk of Urolithiasis

Additions and/or revisions underlined:

In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO and patients treated with placebo. However, FORTEO has not been studied in patients with active urolithiasis. If FORTEO-treated patients have pre-existing hypercalciuria or suspected/known active urolithiasis, consider measuring urinary calcium excretion. Consider the risks and benefits of use in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

5.4 Orthostatic Hypotension

Additions and/or revisions underlined:

FORTEO should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur. In short-term clinical pharmacology studies of FORTEO in healthy volunteers, transient episodes of symptomatic orthostatic hypotension were observed in 5% of volunteers. Typically, these events began within 4 hours of dosing and resolved (without treatment) within a few minutes to a few hours …

5.5 Risk of Digoxin Toxicity

Additions and/or revisions underlined:

Hypercalcemia may predispose patients to digitalis toxicity because FORTEO transiently increases serum calcium. Consider the potential onset of signs and symptoms of digitalis toxicity when FORTEO is used in patients receiving digoxin [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… Men with Primary or Hypogonadal Osteoporosis and Postmenopausal Women with Osteoporosis

Group(s) replaces patient(s)

Table 1: Percentage of Patients with Adverse Events Reported by at Least 2% of FORTEO-Treated Patients and in More FORTEO-Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in Women and Men Adverse Events are Shown Without Attribution of Causality

Laboratory Findings

Serum Calcium — FORTEO transiently increased serum calcium … different from pretreatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was 11% of women and 6% of men treated with FORTEO compared to 2% of women and 0% of the men treated with placebo. The percentage of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.

There was no increase in mortality in the FORTEO group compared to the active control group. The incidence of serious adverse events was 21% in FORTEO patients and 18% in active control patients …

Newly added subsection:

6.2 Immunogenicity

As with all peptides, there is 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 in the studies described below with the incidence of antibodies in other studies or to other teriparatide products may be misleading.

In the clinical trial of postmenopausal women with osteoporosis [see Clinical Studies (14.1)], antibodies that cross reacted with teriparatide were detected in 3% of women (15/541) who received FORTEO. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response.

6.3 Postmarketing Experience

Additions and/or revisions underlined:

Adverse Reactions from Postmarketing Spontaneous Reports

The following adverse reactions have been identified during postapproval use of FORTEO …

… Adverse Reactions from Observational Studies to Assess Incidence of Osteosarcoma

Two osteosarcoma surveillance safety studies (U.S. claims-based database studies) were designed to obtain data on the incidence rate of osteosarcoma among FORTEO-treated patients. In these two studies, three and zero osteosarcoma cases were identified among 379,283 and 153,316 FORTEO users, respectively. The study results suggest a similar risk for osteosarcoma between FORTEO users and their comparators. However, the interpretation of the study results calls for caution owing to the limitations of the data sources which do not allow for complete measurement and control for confounders.

7 Drug Interactions

7.1 Digoxin

Additions and/or revisions underlined:

Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. FORTEO may transiently increase serum calcium. Consider the potential onset of signs and symptoms of digitalis toxicity when FORTEO is used in patients receiving digoxin [see Warnings and Precaution (5.5) and Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

It is not known whether teriparatide is excreted in human milk, affects human milk production, or has effects on the breastfed infant. Avoid FORTEO use in women who are breastfeeding.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of FORTEO have not been established in pediatric patients. Pediatric patients are at higher baseline risk of osteosarcoma because of open epiphyses [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the patients who received FORTEO in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and older and 23% were 75 years of age and older. Of the patients who received FORTEO in the trial of 437 men with primary or hypogonadal osteoporosis, 39% were 65 years of age and over and 13% were 75 years of age and over. Of the 214 patients who received FORTEO in the glucocorticoid induced osteoporosis trial, 28% were 65 years of age and older and 9% were 75 years of age and older. No overall differences in safety or effectiveness of FORTEO have been observed between patients 65 years of age and older and younger adult patients.

8.7 Renal Impairment

Additions and/or revisions underlined:

In 5 patients with severe renal impairment (CrCl<30 mL/minute), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. It is unknown whether FORTEO alters the underlying metabolic bone disease seen in chronic renal impairment [see Clinical Pharmacology (12.3)].

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

MEDICATION GUIDE

Formatting has changed with extensive changes throughout; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide and the User Manual) before starting FORTEO and each time the prescription is renewed. Failure to follow the instructions may result in inaccurate dosing.

Osteosarcoma

Patients should be made aware that in rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor). Although cases of osteosarcoma have been reported in patients using FORTEO no increased risk of osteosarcoma was observed in adult humans treated with FORTEO [see Warnings and Precautions (5.1)].

Hypercalcemia

Instruct patients taking FORTEO to contact a health care provider if they develop persistent symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness) [see Warnings and Precautions (5.2)].

Orthostatic Hypotension

When initiating FORTEO treatment, instruct patients to be prepared to immediately sit or lie down during or after administration in case they feel lightheaded or have palpitations after the injection. Instruct patients to sit or lie down until the symptoms resolve. If symptoms persist or worsen, instruct patients to consult a healthcare provider before continuing treatment [see Warnings and Precautions (5.4)].

Other Osteoporosis Treatment Modalities

Patients should be informed regarding the roles of supplemental calcium and/or vitamin D.

Use of the Prefilled Delivery Device (Pen)

Instruct patients and caregivers who administer FORTEO on how to properly use the delivery device (refer to User Manual), to properly dispose of needles, and not to share their prefilled delivery device with other patients. Instruct patients and caregivers who administer FORTEO that the contents of the delivery device should not be transferred to a syringe.

Inform patients that each FORTEO delivery device can be used for up to 28 days. After the 28-day use period, instruct patients to discard the FORTEO delivery device, even if it still contains some unused solution. Instruct patients not to use FORTEO after the expiration date printed on the delivery device and packaging.

10/03/2019 (SUPPL-52)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

There are no available data on FORTEO use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider discontinuing FORTEO when pregnancy is recognized.

In animal reproduction studies, teriparatide increased skeletal deviations and variations in mouse offspring at subcutaneous doses equivalent to more than 60 times the recommended 20 mcg human daily dose (based on body surface area, mcg/m^2), and produced mild growth retardation and reduced motor activity in rat offspring at subcutaneous doses equivalent to more than 120 times the human dose.

The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the US general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In animal reproduction studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses equivalent to 8 to 267 times the human dose (based on body surface area, mcg/m^2). At subcutaneous doses greater than or equal to 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received teriparatide during organogenesis at subcutaneous doses 16 to 540 times the human dose, the fetuses showed no abnormal findings.

In a perinatal/postnatal study in pregnant rats dosed subcutaneously from organogenesis through lactation, mild growth retardation was observed in female offspring at doses greater than or equal to 120 times the human dose. Mild growth retardation in male offspring and reduced motor activity in both male and female offspring were observed at maternal doses of 540 times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

It is not known whether teriparatide is excreted in human milk, affects human milk production, or has effects on the breastfed infant.

Because of the potential for osteosarcoma shown with teriparatide in animal studies, advise patients that breastfeeding is not recommended during treatment with FORTEO.

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

MEDICATION GUIDE

(addition of medication guide; please refer to labeling for complete information)