DRUG INTERACTIONS-(summary)

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

• NATPARA was not studied in patients with hypoparathyroidism 

DRUG INTERACTIONS-(d.etails)-

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.

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.

BRIEF.SUMMARY

PARATHYROID HORMONE- (Jan 2015)

Indn-        to control hypocalcemia in patients with hypoparathyroidism.

Comp-     for subcutaneous use For injection: 25 mcg, 50 mcg, 75 mcg, or 100 mcg.  The starting dose of NATPARA is 50 mcg injected once daily . When starting NATPARA, decrease dose of active vitamin D by Medication Guide 50%, if serum calcium is above 7.5 mg/dL.

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

CONTRAINDICATIONS-­ • None

WARNINGS-

  • 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

Pat Infm-

1. Potential Risk of Osteosarcoma-

 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.

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Novel Drug Approvals for 2015

1.Name       -  NATPARA

2. Active Ingredient-     Parathyroid Hormone

3. Indication-   NATPARA is a parathyroid hormone indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism.

.

Date of Approval  Jan 2015

HIGHLIGHTS OF PRESCRIBING INFORMATION

 The occurrence of osteosarcoma was 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 in humans receiving a 100 mcg dose of NATPARA. These data could not exclude a risk to humans

.

1 INDICATIONS AND USAGE-

NATPARA is a parathyroid hormone indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism.

Limitations of Use:                                                                                                             • Because of the potential risk of osteosarcoma, NATPARA is recommended only for patients who cannot be well-controlled on calcium supplements and active forms of vitamin D alone.

• NATPARA was not studied in patients with hypoparathyroidism caused by calcium-sensing receptor mutations.

• NATPARA was not studied in patients with acute post-surgical hypoparathyroidism.

should be individualized based on total serum calcium (albumin-corrected) and 24-hr

ADVERSE REACTIONS-

­ prior external beam or implant radiation therapy involving the

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

• NATPARA is available only through a restricted program called the hypocalcemia, headache, hypercalcemia, nausea, hypoaesthesia,  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.  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 of

DOSAGE AND ADMINISTRATION--

 • The dose of NATPARA should be individualized to achieve a serum

• No dose adjustment is recommended in patients =65 years of age, or in calcium level in the lower half of the normal range. (2.1) patients with mild to moderate renal or hepatic impairment.

, • Confirm vitamin D stores are sufficient and serum calcium is above 7.5 8.6, 12.3) mg/dL before starting NATPARA.

• The starting dose of NATPARA is 50 mcg injected once daily in the See Section 17 for PATIENT COUNSELING INFORMATION and thigh. When starting NATPARA, decrease dose of active vitamin D by Medication Guide 50%, if serum calcium is above 7.5 mg/dL.

 • Monitor serum calcium levels every 3 to 7 days after starting or Revised: [m/year] adjusting NATPARA dose and when adjusting either active vitamin D or calcium supplements dose while using NATPARA. 

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.

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.

1. Potential Risk of Osteosarcoma-

 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. 

2. NATPARA REMS 

• 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

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.

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.

5 Digoxin Toxicity [see Warning and Precautions (5.5)]: Instruct patients to: report use of digoxin containing medication, and follow recommended serum calcium monitoring. 

 CLINICAL PHARMACOLOGY -

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.

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

 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

3. Pharmacolgy/Pharmaceutics-

 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.

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.

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.

 USE IN SPECIFIC POPULATIONS-

1. Pregnancy-

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.

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 

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.

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

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

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

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