DRUG INTERACTIONS-(summary)

­ • Because of the potential risk of osteosarcoma, NATPARA is

• Digoxin: Monitor serum calcium more frequently when using recommended only for patients who cannot be well-controlled on NATPARA in patients receiving digoxin. (5.5, 7.2) calcium supplements and active forms of vitamin D alone.

• NATPARA was not studied in patients with hypoparathyroidism caused

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                    SAVAYSA™ safely and effectively.

See full prescribing information for SAVAYSA. SAVAYSA (edoxaban) tablets for oral use

Initial U.S. Approval: 2015-

 WARNING-                                                                                                                      (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CREATININE CLEARANCE (CRCL) > 95 ML/MIN (B) PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC EVENTS (C) SPINAL/EPIDURAL HEMATOMA -

See full prescribing information for complete boxed warning.

(A) REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CRCL > 95 ML/MIN:

SAVAYSA should not be used in patients with CrCL > 95 mL/min.

In the ENGAGE AF-TIMI 48 study, nonvalvular atrial fibrillation patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg once daily compared to patients treated with warfarin. In these patients another anticoagulant should be used 

(B) PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC EVENTS:

Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance 

(C) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may occur in patients treated with SAVAYSA who are receiving neuraxial anesthesia or undergoing spinal puncture.

These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures 

INDICATIONS AND USAGE-

 SAVAYSA is afactor Xa inhibitor indicated: To reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF)

 • Limitation of Use for NVAF SAVAYSA should not be used in patients with creatinine clearance (CrCL) > 95 mL/min because of increased risk of ischemic stroke compared to warfarin at the highest dose studied (60 mg)

 SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant 

-ADVERSE REACTIONS--

­ prior external beam or implant radiation therapy involving the

• The most common adverse reactions associated with NATPARA and skeleton) (5.1) occurring in greater than 10% of individuals were: paresthesia,

• NATPARA is available only through a restricted program called the hypocalcemia, headache, hypercalcemia, nausea, hypoaesthesia, NATPARA REMS Program  diarrhea, vomiting, arthralgia, hypercalciuria and pain in extremity 

CONTRAINDICATIONS-

­ • None 

WARNINGS AND PRECAUTIONS--

­ WARNING: POTENTIAL RISK OF OSTEOSARCOMA

• Potential Risk of Osteosarcoma: Prescribe NATPARA only to patients See full prescribing Information for complete boxed warning who cannot be well-controlled on calcium and active vitamin D. Avoid use of NATPARA in patients who are at increased risk for

• In male and female rats, parathyroid hormone caused an increase in osteosarcoma. (5.1) the incidence of osteosarcoma (a malignant bone tumor) that was

• Severe Hypercalcemia: Monitor serum calcium when starting or dependent on dose and treatment duration. A risk to humans could adjusting NATPARA dose and when making changes to conot be excluded  administered drugs known to raise serum calcium.

• Because of the potential risk of osteosarcoma, prescribe NATPARA

• Severe Hypocalcemia: Can occur with interruption or discontinuation of only to patients who cannot be well-controlled on calcium and active NATPARA treatment. Monitor serum calcium and replace calcium and forms of vitamin D and for whom the potential benefits are vitamin D.  considered to outweigh the potential risk.

 • Digoxin Toxicity: Hypercalcemia increases the risk of digoxin toxicity.

• Avoid use of NATPARA in patients who are at increased baseline In patients using NATPARA concomitantly with digoxin, monitor serum risk for osteosarcoma (including those with Paget’s disease of bone calcium more frequently and increase monitoring when initiating or or unexplained elevations of alkaline phosphatase, pediatric and adjusting NATPARA dose.  young adult patients with open epiphyses, patients with hereditary disorders predisposing to osteosarcoma or patients with a history o

DOSAGE FORMS AND STRENGTHS-

­ These highlights do not include all the information needed to use NATPARA is supplied as a multiple dose, dual-chamber glass cartridge NATPARA safely and effectively. See full prescribing information for containing a sterile lyophilized powder and a sterile diluent for reconstitution NATPARA. in four dosage strengths. NATPARA® (parathyroid hormone) for injection, for subcutaneous use For injection: 25 mcg, 50 mcg, 75 mcg, or 100 mcg.

Initial U.S. Approval: [01/23/2015]

17 PATIENT COUNSELING INFORMATION-

 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. 22Jan2015 Reference ID: 3691249 1.14.1.3

Draft Labeling Text NATPARA® (parathyroid hormone) for injection Page 20 of 21 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 PatientPrescriber Acknowledgment Form

• NATPARA is only available through certified pharmacies, provide information to your patients about how they will receive prescriptions:

o Submit the NATPARA prescription to the NATPARA REMS Program Coordinating Center (by fax or email)

o 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

o 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 o 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 22Jan2015 Reference ID: 3691249 1.14.1.3 Draft Labeling Text NATPARA® (parathyroid hormone) for injection Page 21 of 21 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.

U.S. License Number 1908 Q-Cliq™ is a trademark and NATPARA® is a registered trademark of NPS Pharmaceuticals, Inc. Ultra-Fine™ is a trademark of Becton-Dickinson. NATPARA is covered by US Patent No. 5,496,801

Manufactured for: NPS Pharmaceuticals, Inc. 550 Hills Drive Bedminster, NJ 07921 For information about NATPARA contact: NPS Pharmaceuticals, Inc. 550 Hills Drive Bedminster, NJ 07921 USA 1-855-NATPARA www.NATPARA.com

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action NATPARA is a parathyroid hormone. Parathyroid hormone raises serum calcium by increasing renal tubular calcium reabsorption, increasing intestinal calcium absorption (i.e., by converting 25 OH vitamin D to 1,25 OH2 vitamin D) and by increasing bone turnover which releases calcium into the circulation. 22Jan2015 Reference ID: 3691249 1.14.1.3 Draft Labeling Text NATPARA® (parathyroid hormone) for injection Page 13 of 21 12.2 Pharmacodynamics The pharmacodynamics in subjects with hypoparathyroidism after single subcutaneous administration of 50 and 100 mcg dose of NATPARA in the thigh were evaluated. Treatment with NATPARA increases serum calcium levels (Figure 2). The increase in serum calcium levels in hypoparathyroidism subjects occurs in a dose-related manner. Mean peak serum calcium levels are reached between 10 and 12 hours following a single subcutaneous injection and the increase in serum calcium above baseline is sustained for more than 24 hours after administration. The maximum mean increases of serum calcium, which occurred at 12 hours, were approximately 0.5 mg/dL and 0.7 mg/dL from baseline with the 50 mcg and 100 mcg doses, respectively. The mean calcium intake for the 50 and 100 mcg doses was 1700 mg [see Clinical Pharmacology (12.3)]. 12.3 Pharmacokinetics Following single subcutaneous injections of NATPARA at 50 mcg and 100 mcg in subjects with hypoparathyroidism, peak plasma concentrations (mean Tmax) of NATPARA occurs within 5 to 30 minutes and a second usually smaller peak at 1 to 2 hours. The plasma AUC increased in a dose proportional manner from 50 mcg to 100 mcg. The apparent terminal half-life (t1/2) was 3.02 and 2.83 hours for the 50 and 100 mcg dose, respectively. Mean unadjusted concentration-time profiles of parathyroid hormone in plasma following SC administration of 100 mcg of NATPARA are presented in Figure 2. One 100 mcg dose of NATPARA provides a 24-hour calcemic response in hypoparathyroidism subjects. 22Jan2015 Reference ID: 3691249 1.14.1.3 Draft Labeling Text NATPARA® (parathyroid hormone) for injection Page 14 of 21 Figure 2 Mean (±SE) Unadjusted Plasma Parathyroid Hormone and Albumin-Corrected Serum Calcium Concentration Following 100 mcg SC Administration in Subjects with Hypoparathyroidism Absorption: NATPARA administered subcutaneously has an absolute bioavailability of 53%. Distribution: NATPARA has a volume of distribution of 5.35 L at steady state. Metabolism: In vitro and in vivo studies demonstrated that the clearance of parathyroid hormone is primarily a hepatic process with a lesser role played by the kidneys. Excretion: In the liver, most of the intact parathyroid hormone is cleaved by cathepsins. In the kidney, a small amount of parathyroid hormone binds to physiologic PTH-1 receptors, but most is filtered at the glomerulus. C-terminal fragments are also cleared efficiently by glomerular filtration. Hepatic Impairment: 22Jan2015 Reference ID: 3691249 1.14.1.3 Draft Labeling Text NATPARA® (parathyroid hormone) for injection Page 15 of 21 A pharmacokinetic study was conducted in 6 men and 6 women with moderate hepatic impairment (Child-Pugh Classification of 7-9 [Grade B]) as compared with a matched group of 12 subjects with normal hepatic function. Following a single 100-mcg subcutaneous dose, the mean Cmax and baselinecorrected Cmax values were 18% to 20% greater in the moderately impaired subjects than in those with normal function. There were no apparent differences in the serum total calcium concentration-time profiles between the 2 hepatic function groups. No dose adjustment for NATPARA is recommended in patients with mild to moderate hepatic impairment. Renal Impairment: Pharmacokinetics following a single NATPARA 100 mcg subcutaneous dose was evaluated in 16 subjects with normal renal function (creatinine clearance (CLcr) > 90 mL/min) and 16 subjects with renal impairment. The mean maximum concentration (Cmax) of parathyroid hormone following administration of 100 mcg NATPARA in subjects with mild (CLcr 60 to 90 mL/min) and moderate (CLcr 30 to 60 mL/min) renal impairment was approximately 22% higher than that observed in subjects with normal renal function. Exposure to parathyroid hormone as measured by AUC0-last and baselinecorrected AUC0-last was approximately 3.9% and 2.5%, respectively, higher than that observed for subjects with normal renal function. No studies were conducted in patients with severe renal impairment or in renal impairment patients on dialysis. Age, Sex, Race, and Weight: Based on population pharmacokinetic analysis, age, sex, race, and body weight did not significantly affect the NATPARA pharmacokinetics.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 104-week carcinogenicity study in rats, parathyroid hormone was given subcutaneously at doses of 10, 50 and 150 mcg/kg/day. These doses resulted in systemic exposures that were, respectively 3 to 71 times higher than systemic exposure observed in humans following a subcutaneous dose of 100 mcg/day based on AUC. Sys

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

1 Pregnancy 22Jan2015 Reference ID: 3691249 1.14.1.3 Draft Labeling Text NATPARA® (parathyroid hormone) for injection Page 11 of 21

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)].

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