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2015年1月23日，美国FDA批准Natpara（甲状旁腺激素）用于控制甲状旁腺功能减退患者的低血钙症，这是一种罕见疾病，在美国影响大约6万人。当人体异常分泌低水平的可以帮助调节人体内钙、磷水平的甲状旁腺激素时，就会发生甲状旁腺功能减退。
6. Repeat steps 4 and 5 until target serum calcium levels are within the lower half of the normal range, active vitamin D has been discontinued and calcium supplementation is sufficient to meet daily requirements. 2.4 NATPARA Dose Adjustments The dose of NATPARA may be increased in increments of 25 mcg every four weeks up to a maximum daily dose of 100 mcg if serum calcium cannot be maintained above 8 mg/dL without an active form of vitamin D and/or oral calcium supplementation. The dose of NATPARA may be decreased to as low as 25 mcg per day if total serum calcium is repeatedly above 9 mg/dL after the active form of vitamin D has been discontinued and calcium supplement has been decreased to a dose sufficient to meet daily requirements. After a NATPARA dose change monitor clinical response as well as serum calcium. Adjust active vitamin D and calcium supplements per steps 4-6 above if indicated [see Dosage and Administration (2.3)]. 2.5 NATPARA Maintenance Dose The maintenance dose should be the lowest dose that achieves a total serum calcium (albumin-corrected) within the lower half of the normal total serum calcium range (i.e., approximately 8 and 9 mg/dL), without the need for active forms of vitamin D and with calcium supplementation sufficient to meet daily requirements. Monitor serum calcium and 24-hour urinary calcium per standard of care once a maintenance dose is achieved. 2.6 NATPARA Dose Interruption or Discontinuation Abrupt interruption or discontinuation of NATPARA can result in severe hypocalcemia. Resume treatment with, or increase the dose of, an active form of vitamin D and calcium supplements if indicated in patients interrupting or discontinuing NATPARA, monitor for signs and symptoms of hypocalcemia and serum calcium levels [see Warnings and Precautions (5.4)]. In the case of a missed dose, the next NATPARA dose should be administered as soon as reasonably feasible and additional exogenous calcium should be taken in the event of hypocalcemia. 2.7 Reconstitution and Administration Instructio Patients and caregivers who will administer NATPARA should receive appropriate training and instruction by a trained healthcare professional prior to first use of NATPARA. Follow the Instructions for Use to reconstitute NATPARA using the mixing device for reconstitution and to administer NATPARA using the pen delivery device (i.e., Q-Cliq pen). Inspect NATPARA visually for particulate matter and discoloration prior to administration. Discard the needle in a puncture-resistant container following administration. Store the Q-Cliq pen containing the remaining doses of NATPARA in a refrigerator. All reconstituted NATPARA medication cartridges older than 14 days must be discarded. [see How Supplied/Storage and Handling (16.2)] 3 DOSAGE FORMS AND STRENGTHS NATPARA is supplied as a multiple dose, dual-chamber glass cartridge containing a sterile powder and diluent in 4 dosage strengths.
None. 5 WARNINGS AND PRECAUTIONS 5.1 Potential Risk of Osteosarcoma In male and female rats, parathyroid hormone, caused an increase in the incidence of osteosarcoma (a malignant bone tumor). The occurrence of osteosarcoma was observed to be dependent on parathyroid hormone dose and treatment duration. This effect was observed at parathyroid hormone exposure levels ranging from 3 to 71 times the exposure levels for humans receiving a 100 mcg dose of NATPARA. These data could not exclude a risk to humans [see Nonclinical Toxicology (13.1)]. Because of a potential risk of osteosarcoma, use NATPARA only in patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone and for whom the potential benefits are considered to outweigh this potential risk [see Limitations of Use (1)]. To further mitigate the potential risk of osteosarcoma avoid use of NATPARA in patients who are at increased risk for osteosarcoma such as patients with Paget's disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, patients with hereditary disorders predisposing to osteosarcoma or patients with a prior history of external beam or implant radiation therapy involving the skeleton. Instruct patients to promptly report clinical symptoms (e.g., persistent localized pain) and signs (e.g., soft tissue mass tender to palpation) that could be consistent with osteosarcoma. NATPARA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)]. 5.2 NATPARA REMS Program Because of the potential risk of osteosarcoma associated with NATPARA therapy, NATPARA is available only through a restricted REMS program called the NATPARA REMS Program. Under the NATPARA REMS Program, only certified healthcare providers can prescribe and only certified pharmacies can dispense NATPARA. Further information is available at www.NATPARAREMS.com or by telephone at 1-855-NATPARA. 5.3 Hypercalcemia Severe hypercalcemia has been reported with NATPARA. In the pivotal trial, 2 patients randomized to NATPARA required administration of IV fluids to correct hypercalcemia. The risk is highest when starting or increasing the dose of NATPARA. Monitor serum calcium and patients for signs and symptoms of hypercalcemia. Treat hypercalcemia per standard practice and consider holding and/or lowering the dose of NATPARA if severe hypercalcemia occurs [see Dosage and Administration (2) and Adverse Reactions (6.1)]. 5.4 Hypocalcemia Severe hypocalcemia has been reported with NATPARA. The risk is highest when NATPARA is withheld, missed or abruptly discontinued, but can occur at any time. Monitor serum calcium and patients for signs and symptoms of hypocalcemia. Resume treatment with, or increase the dose of, an active form of vitamin D or calcium supplements or both if indicated in patients interrupting or discontinuing NATPARA to prevent severe hypocalcemia [see Dosage and Administration (2.6) and Adverse Reactions (6.1)]. 5.5 Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds The inotropic effects of digoxin are affected by serum calcium levels. Hypercalcemia of any cause may predispose to digoxin toxicity. In patients using NATPARA concomitantly with digitalis compounds, monitor serum calcium and digoxin levels and patients for signs and symptoms of digitalis toxicity. Adjustment of digoxin and/or NATPARA may be needed. No drug-drug interaction study has been conducted with digoxin and NATPARA [see Drug Interactions (7) and Adverse Reactions (6.1)]. 6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: Osteosarcoma [see Boxed Warning, Warnings and Precautions (5.1)] Hypercalcemia [see Warnings and Precautions (5.3)] Hypocalcemia [see Warnings and Precautions (5.4)] 6.1 Adverse Reactions in Clinical Trials for Hypoparathyroidism Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. NATPARA was studied in a placebo-controlled trial [see Clinical Studies (14)]. The data described in Table 1 below reflect exposure to NATPARA in 84 patients, including 78 exposed for 24 weeks. The mean age of the trial population was 47 years and ranged from 19 to 74 years old. Seventy-nine percent (79%) were females. Ninety six percent (96%) were Caucasian, 0.8% were Black, and 1.6% were Asian. Patients had had hypoparathyroidism for on average 15 years and hypoparathyroidism was caused by post-surgical complications in 71% of cases, idiopathic hypoparathyroidism in 25% of cases, DiGeorge Syndrome in 3% of cases, and auto-immune hypoparathyroidism in 1% of cases. Prior to trial enrollment, participants were receiving a median (interquartile range) daily oral calcium dose of 2000 (1250, 3000) mg and a median daily oral active vitamin D dose equivalent to 0.75 (0.5, 1) mcg of calcitriol. The mean eGFR at baseline was 97.4 mL/min/1.73 m2 and 45%, 10% and 0% had mild, moderate and severe renal impairment, respectively, at baseline. During the trial, most patients received 100 mcg and the dose range was 50 to 100 mcg administered subcutaneously once daily in the thigh. Table 1 lists common adverse reactions associated with NATPARA use in the clinical trial. Common adverse reactions were reactions that occurred in ≥5% of subjects and occurred more commonly on NATPARA than on placebo. Table 1: Common Adverse Reactions associated with NATPARA use in Subjects with Hypoparathyroidism
Hypercalcemia In the overall pivotal trial a greater proportion of patients on NATPARA had albumin-corrected serum calcium above the normal range (8.4 to 10.6 mg/dL). During the entire trial duration 3 patients on NATPARA and 1 patient on placebo had a calcium level above 12 mg/dL. Table 2 displays the number of subjects who had albumin-corrected serum calcium levels above the normal range (8.4 to 10.6 mg/dL) by study treatment period in the placebo-controlled study based on routine monitoring at each trial visit. More patients randomized to NATPARA had hypercalcemia in both phases of the study (note: all trial participants underwent a 50% reduction in active vitamin D dose at randomization). Table 2 Proportion of Subjects with Albumin-Corrected Serum Calcium Greater Than Upper Limit of Normal (10.6 mg/dL) During the Treatment Period
Table 3 displays the number of subjects who had albumin-corrected serum calcium levels below 8.4 mg/dL by treatment period in the placebo-controlled study based on routine monitoring at each trial visit. More patients randomized to placebo had hypocalcemia of less than 7 mg/dL in the titration phase (note: all trial participants underwent a 50% reduction in active vitamin D dose at randomization). More patients randomized to NATPARA had hypocalcemia of less than 7 mg/dL in the dose maintenance phase. Table 3 Proportion of Subjects with Albumin-Corrected Serum Calcium Below the Lower Limit of Normal (8.4 mg/dL) During the Treatment Period
Hypercalciuria Treatment with NATPARA did not lower 24 hour urinary calcium excretion in the placebo-controlled trial. The proportion of subjects with hypercalciuria (defined as a urine calcium levels of > 300 mg/24 hours) was similar at baseline and trial end in the NATPARA and placebo groups. The median (IQR) 24-hour Urine Calcium at trial end was similar between NATPARA [231 (168-351) mg/24 hours], and placebo [232 (139-342) mg/24 hours]. At trial end, serum calcium values between NATPARA and placebo were also similar. Risk of hypercalciuria throughout the trial was related to serum calcium levels. To minimize the risk of hypercalciuria, NATPARA should be dosed to a target albumin-corrected total serum calcium within the lower half of the normal range (i.e., between 8 and 9 mg/dL) [See Dosage and Administration (2.1)]. 6.2 Immunogenicity NATPARA may trigger the development of antibodies. In the placebo-controlled study in adults with hypoparathyroidism, the incidence of anti-PTH antibodies was 8.6% (3/35) and 5.9% (1/17) in subjects who received subcutaneous administration of 50 to 100 mcg NATPARA or placebo once daily for 24 weeks, respectively. Across all clinical studies in subjects with hypoparathyroidism following treatment with NATPARA for up to 2.6 years, the immunogenicity incidence rate was 16.1% (14/87). These 14 subjects had low titer anti-PTH antibodies and of these, 3 subjects subsequently became antibody negative. One of these subjects had antibodies with neutralizing activity; this subject maintained a clinical response with no evidence of immune-related adverse reactions. Anti-PTH antibodies did not appear to affect efficacy or safety during the clinical trials but their longer-term impact is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying diseases. For these reasons, comparison of the incidence of antibodies to NATPARA with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS 7.1 Alendronate Co-administration of alendronate and NATPARA leads to reduction in the calcium sparing effect, which can interfere with the normalization of serum calcium. Concomitant use of NATPARA with alendronate is not recommended. 7.2 Digoxin NATPARA causes transient increase in calcium and therefore, concomitant use of NATPARA and cardiac glycosides (e.g. digoxin) may predispose patients to digitalis toxicity if hypercalcemia develops. Digoxin efficacy is reduced if hypocalcemia is present. In patients using NATPARA concomitantly with digoxin, carefully monitor serum calcium and digoxin levels, and patients for signs and symptoms of digoxin toxicity. Adjustment of digoxin and/or NATPARA may be needed. No drug-drug interaction study has been conducted with digoxin and NATPARA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Developmental effects were observed in a peri-/post-natal study in pregnant rats given subcutaneous doses of 100, 300, 1000 mcg/kg/day from organogenesis through lactation, while entire stillborn litters were observed in the 300 mcg/kg/day group (34 times the 100 mcg/day clinical dose based on AUC ). 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). Because animal reproduction studies are not always predictive of human response, NATPARA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Nonclinical Toxicology (13.2)]. 8. 3 Nursing Mothers It is unknown whether NATPARA is excreted in human milk. In rats, mean parathyroid hormone concentration in milk was approximately 10 ng/mL at a dose of 1000 mcg/kg/day, 42 times lower in milk than in plasma. For nursing mothers, consideration should be made whether discontinuing nursing or NATPARA is warranted, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in patients less than 18 years of age has not been established. Avoid use of NATPARA in patients who are at increased baseline risk for osteosarcoma including pediatric and young adult patients with open epiphyses [see Boxed Warning and Warnings and Precautions (5.1)]. 8.5 Geriatric Use Clinical studies of NATPARA did not include sufficient numbers of subjects aged 65 and over to determine whether response in these subjects is different from younger subjects. In general, dose selection for elderly individuals should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [See Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Clinical studies of NATPARA did not include sufficient numbers of subjects with moderate and severe renal impairment to determine whether they respond differently from subjects with mild renal impairment or normal renal function. Some of the mechanisms of action of NATPARA (e.g., conversion of 25-OH vitamin D to 1,25-OH2 vitamin D) are dependent on renal function. NATPARA is eliminated by the kidney and maximum drug levels increased with renal impairment [See Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Accidental overdose in studies in hypoparathyroidism occurred in 1 subject who received a 150 mcg dose and experienced mild palpitations. Serum calcium 24 hours later was 10.3 mg/dL. In the event of overdose, the patient should be carefully monitored for hypercalcemia by a medical professional [see Adverse Reactions (6.1)]. 11 DESCRIPTION The active ingredient in NATPARA, parathyroid hormone, is produced by recombinant DNA technology using a modified strain of Escherichia coli. Parathyroid hormone, has 84 amino acids and a molecular weight of 9425 daltons; The amino acid sequence for parathyroid hormone is shown below. Figure 1: Amino Acid Sequence of Parathyroid Hormone
Based on Fisher's exact test Table 7: Proportion of Patients with Calcium and Active Vitamin D Dose Reduction and Albumin-Corrected Serum Calcium between 7 and 10.6 mg at End of Treatment – ITT Population
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NATPARA (parathyroid hormone) for injection for subcutaneous use is supplied as a medication cartridge, which is comprised of a multiple dose, dual-chamber glass cartridge containing a sterile lyophilized powder and a sterile diluent, within a plastic cartridge holder. The medication cartridge is available in 4 dosage strengths (25, 50, 75, and 100 mcg/dose). The 25 mcg/dose cartridge contains 0.40 mg parathyroid hormone; the 50 mcg/dose cartridge contains 0.80 mg parathyroid hormone; the 75 mcg/dose cartridge contains 1.21 mg parathyroid hormone; the 100 mcg/dose cartridge contains 1.61 mg parathyroid hormone. NATPARA is supplied in the following packages: 2 cartridges of 25 mcg/dose strength (NDC 68875-0202-2) 2 cartridges of 50 mcg/dose strength (NDC 68875-0203-2) 2 cartridges of 75 mcg/dose strength (NDC 68875-0204-2) 2 cartridges of 100 mcg/dose strength (NDC 68875-0205-2) The disposable NATPARA medication cartridge is designed for use with a reusable mixing device for product reconstitution and a reusable Q-Cliq pen injector for drug delivery. The Q-Cliq pen is designed to deliver a fixed volumetric dose of 71.4 µL. Using the Q-Cliq pen, each NATPARA medication cartridge delivers 14 doses; each dose contains 25, 50, 75, or 100 mcg of NATPARA depending on the product dosage strength. Designed for use with 31G × 8 mm BD Ultra-Fine™ Pen Needles. The mixing device, provided in a separate carton, is designed to enable reconstitution of the product before the first use of each cartridge. The mixing device can be used to reconstitute up to 6 NATPARA medication cartridges. The Q-Cliq pen, packaged in a separate carton, can be used for up to 2 years of daily treatment by replacing the reconstituted cartridge every two weeks (14 days). Instructions for use of the mixing device and the Q-Cliq pen are provided with the NATPARA medication cartridges. 16.2 Storage and Handling Prior to reconstitution, the dual-chamber NATPARA medication cartridge should be stored in the package provided at refrigerated temperature, 36 to 46°F (2 to 8°C). After reconstitution, the medication cartridge should be stored in the Q-Cliq pen under refrigeration at 36 to 46°F (2 to 8°C). The reconstituted product can be used for up to 14 days under these conditions. Store away from heat and light. Avoid exposure to elevated temperatures. Discard reconstituted NATPARA medication cartridges after 14 days. Do not freeze or shake. Do not use NATPARA if it has been frozen or shaken. The mixing device and empty Q-Cliq pen can be stored at room temperature. Safely discard needles. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for Use) General Counseling Information – Prior to treatment, patients should fully understand the risks and benefits of NATPARA. Ensure that all patients receive the Medication Guide and Instructions for Use document prior to initiating NATPARA therapy. 17.1 Potential Risk of Osteosarcoma [see Warning and Precautions (5.1)] Advise patients that the active ingredient in NATPARA, parathyroid hormone, caused an increase in the incidence of osteosarcoma (a malignant bone tumor) in male and female rats in dedicated lifelong carcinogenicity studies and that the risk of osteosarcoma in rats was dependent on parathyroid hormone dose administered, on treatment duration and occurred at exposure levels close to the clinical exposure range. Based on these findings NATPARA may carry a potential risk to humans. Patients should be advised that because of a potential risk of osteosarcoma, NATPARA is only recommended for patients who cannot be well-controlled on oral calcium supplementation and on active forms of Vitamin D. In addition, use of NATPARA should be avoided in patients who have risk factors for osteosarcoma unless the benefits of using NATPARA in these patients are determined to outweigh this potential risk. Instruct patients to promptly report signs and symptoms of possible osteosarcoma such as persistent localized pain or occurrence of a new soft tissue mass that is tender to palpation. 17.2 NATPARA REMS [see Warning and Precautions (5.1, 5.2)] NATPARA is available only through a restricted program called the NATPARA REMS Program, because of the potential risk of osteosarcoma. Counsel patients on the benefits and risks of NATPARA using the NATPARA Patient Brochure Patients must sign the NATPARA REMS Patient-Prescriber Acknowledgment Form. Provide patient with a copy of the NATPARA Patient Brochure and NATPARA REMS Patient-Prescriber Acknowledgment Form NATPARA is only available through certified pharmacies, provide information to your patients about how they will receive prescriptions: Submit the NATPARA prescription to the NATPARA REMS Program Coordinating Center (by fax or email) The REMS Program Coordinating Center will send the prescription to a certified pharmacy to fill after verifying that the prescriber is certified and a Patient-Prescriber Acknowledgment Form is on record The REMS Program Coordinating Center will call the patient and provide the name and phone number of the certified pharmacy that will be dispensing NATPARA The certified pharmacy will contact the patient to arrange the date to ship NATPARA once the prescription is filled 17.3 Severe Hypercalcemia [see Warning and Precautions (5.3)] Instruct patients that severe hypercalcemia can occur when starting or adjusting NATPARA dose and/or when making changes to co-administered drugs known to raise serum calcium. Instruct patients to: report symptoms of hypercalcemia promptly, report any changes to co-administered drug(s) known to influence calcium levels and follow recommended serum calcium monitoring. 17.4 Severe Hypocalcemia [see Warning and Precautions (5.4)] Instruct patients that severe hypocalcemia can occur if NATPARA dosing is abruptly interrupted or discontinued. Instruct patients to: report symptoms of hypocalcemia promptly, report interruption in NATPARA dosing and follow recommended serum calcium monitoring. In the event of NATPARA dose interruption patients should contact their healthcare provider as their doses of active vitamin D and calcium supplementation may need adjustment. 17.5 Digoxin Toxicity [see Warning and Precautions (5.5)] Instruct patients to: report use of digoxin containing medication, and follow recommended serum calcium monitoring. 17.6 Dosing Instructions Instruct patients to read the Instructions for Use document carefully. The patient or caregiver should be instructed by a physician or an appropriately qualified healthcare professional in the proper technique for administering subcutaneous injections using the mixing device and the Q-Cliq pen, including the use of aseptic technique. The patient and caregiver should be cautioned that needles must not be re-used and instructed in safe disposal procedures. A puncture-resistant container for disposal of used needles should be supplied to the patient along with instructions for safe disposal of the full container. Instruct patients to never share their devices with other patients. Advise patients to never transfer the contents of the delivery device to a syringe. After reconstitution, each NATPARA medication cartridge can be used for 14 subcutaneous injections. After the use period, only the cartridge should be discarded. The Q-Cliq pen can be used for up to 2 years by replacing the reconstituted medication cartridge every two weeks (14 days). 17.7 Common Adverse Reactions [see Adverse Reactions (6.1)] Inform patients that the most common adverse reactions occurring in patients on NATPARA were paresthesia, hypocalcemia, headache, hypercalcemia, nausea, hypoaesthesia, diarrhea, vomiting, arthralgia, hypercalciuria and pain in extremity. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d11fba31-0a6c-11e3-8ffd-0800200c9a66 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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2015年1月23日，美国FDA批准Natpara（甲状旁腺激素）用于控制甲状旁腺功能减退患者的低血钙症，这是一种罕见疾病，在美国影响大约6万人。当人体异常分泌低水平的可以帮助调节人体内钙、磷水平的甲状旁腺 ... 责任编辑：admin |
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