Drug Safety-related Labeling Changes (SrLC)
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Guide
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.
NATPARA (BLA-125511)
(PARATHYROID HORMONE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/01/2020 (SUPPL-20)
5 Warnings and Precautions
5.2 NATPARA REMS ProgramAdditions and/or revisions underlined:
Further information is available at www.NATPARAREMS.com or by telephone at 1-855-NATPARA (1-855-628-7272).
8 Use in Specific Populations
8.1 Pregnancy
PLLR conversion; newly added information:
Risk Summary
Available data with NATPARA Injection use in pregnant women are insufficient to inform a drug associated risk of birth defects, miscarriage or adverse maternal or fetal outcomes. There are disease associated risks to the mother and the fetus related to hypocalcemia in pregnancy. (see Clinical Considerations). In animal reproduction studies, no adverse developmental effects were observed when pregnant rats and rabbits were administered parathyroid hormone subcutaneously during the period of organogenesis at doses resulting in 123 times and 8 times, respectively, the human exposure at the 100 mcg/day clinical dose. When female rats were administered parathyroid hormone subcutaneously prior to birth and continuing to weaning at doses resulting in 10 times the human exposure at the 100 mcg/day clinical dose, increased incidence of dehydration, broken palate and palate injuries related to incisor misalignment and mortality were observed in offspring (see Data).
All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. In the
U.S. general population, the estimated major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and Embryo/Fetal Risk
Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia.
Fetal/Neonatal adverse reactions
Infants born to mothers with hypocalcemia can have associated fetal and neonatal hyperparathyroidism, which in turn can cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica and neonatal seizures. Infants born to mothers with hypocalcemia should be carefully monitored for signs of hypocalcemia or hypercalcemia, including neuromuscular irritability (ranging from myotonic jerks to seizures), apnea, cyanosis and cardiac rhythm disorders.
Data
Animal Data
In pregnant rats given subcutaneous doses up to 1000 mcg/kg/day during organogenesis there were no findings observed at 123 times the 100 mcg/day clinical dose based on AUC. In pregnant rabbits given subcutaneous doses of 5, 10 and 50 mcg/kg/day during organogenesis, various skeletal alterations including incomplete ossification in <35% of litters given 10 mcg/kg/day which were statistically significant but within historical control range at exposures 8 times the 100 mcg/kg/day clinical dose. There was a fetus with spina bifida in the 50 mcg/kg/day dose group at 72 times the 100 mcg/day clinical dose based on AUC. Given the association of folic acid deficiency and neural tube defects this finding may be related to decreased body weight and food consumption in the pregnant rabbits.
Additions and/or revisions underlined:
Developmental effects were observed in a peri /postnatal study in pregnant rats given subcutaneous doses of 100, 300, 1000 mcg/kg/day from organogenesis through lactation while an entire litter was stillborn in the 300 mcg/kg/day group (34 times the 100 mcg/day clinical dose based on AUC) and an entire litter from the 1000 mcg/kg/day (123 times the 100 mcg/day clinical dose based on AUC) was dead by postnatal day 4. Increased incidence of morbidity associated with dehydration, broken palate and palate injuries related to incisor misalignment and mortality were found in pups from litters given 100 mcg/kg/day (10 times the 100 mcg/day clinical dose based on AUC). At 300 mcg/kg/day there was a litter with kidney dilatation and another with an extra liver lobe. There was a single pup with a diaphragmatic hernia from a litter exposed to 1000 mcg/kg/day.
8.2 Lactation
PLLR conversion; additions and/or revisions underlined:
Risk Summary
There are no data available on the presence of parathyroid hormone in the breast milk, the effects on the breastfed infant or the effects on milk production. Parathyroid hormone is present in the milk of lactating 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 NATPARA and any potential adverse effects on the breastfed child from NATPARA or from the underlying maternal condition.
Clinical Considerations
Infants exposed to parathyroid hormone through breast milk should be monitored for signs and symptoms of hypercalcemia or hypocalcemia. Monitoring of serum calcium in the infant should be considered.
Data
Animal Data
In a lactation transfer study where rats were given subcutaneous doses of 300 and 1000 mcg/kg/day from day 17 of gestation through day 16 of lactation, mean parathyroid hormone concentration in milk was approximately 10 ng/mL at the dose of 1000 mcg/kg/day, 42 times lower in milk than in plasma. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
What is the most important information I should know about NATPARA?
NATPARA is only available through the NATPARA Risk Evaluation and Mitigation Strategy
(REMS) Program. The purpose of the NATPARA REMS program is to inform patients about the
potential risk of osteosarcoma associated with the use of NATPARA. For more information about this
REMS program, call 1-855-NATPARA
(1-855-628-7272) or go to www.NATPARAREMS.com.
NATPARA may cause serious side effects, including: …
Newly added information:
Lactation
Advise women that infants exposed to parathyroid hormone through breast milk should be monitored for symptoms of hypercalcemia or hypocalcemia.