Natpara

Use the missed dose as soon as you remember it and call your doctor immediately. Your doctor may tell you to take more calcium. Continue your regular dosing schedule the next day.

Serious side effects have been reported with Natpara including the following:

• Osteosarcoma (a type of bone cancer). Natpara should not be used in patients with an increased risk of osteosarcoma.
• Severe hypercalcemia (high levels of calcium in the blood). Calcium levels should be monitored while patients are receiving Natpara.
• Severe hypocalcemia (low levels of calcium in the blood). Hypocalcemia can occur when Natpara therapy is interrupted or discontinued. Calcium levels should be monitored while patients are receiving Natpara.

Do not take Natpara if you:

• are allergic to Natpara or to any of its ingredients.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Natpara crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Natpara.

• Store Natpara cartridges (mixed and unmixed) in the refrigerator, between 36°F and 46°F (2°C and 8°C). Do not freeze Natpara.
• Store away from excess heat and light.
• Keep this and all medications out of the reach of children.

In animal studies, parathyroid hormone caused bone cancer. However, it is not known whether these effects would occur in humans. Ask your doctor about your risk.

In animal studies, parathyroid hormone caused bone cancer. However, it is not known whether these effects would occur in humans. Ask your doctor about your risk.

To make sure parathyroid hormone is safe for you, tell your doctor if you have:

• high levels of calcium in your blood;

• high levels of alkaline phosphatase in your blood;

• a history of bone cancer;

• Paget's disease or other bone disorders; or

• if you have ever had a radiation treatment.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether parathyroid hormone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Parathyroid hormone is not approved for use by anyone younger than 18 years old.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• new or unusual pain that is ongoing;

• swelling or tender lumps under your skin;

• high calcium--nausea, vomiting, constipation, increased thirst or urination, muscle pain or weakness, bone pain, confusion, and feeling tired or restless; or

• low calcium--numbness or tingly feeling around your mouth, fast or slow heart rate, muscle tightness or contraction, overactive reflexes.

Common side effects may include:

• tingling, burning, or prickly feeling in your skin;

• headache;

• nausea, vomiting, diarrhea; or

• joint pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of parathyroid hormone is restricted.1 4 (See Restricted Distribution Program under Dosage and Administration.)

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.

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.

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)].

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.

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)].

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)].

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)].

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.

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)].

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.

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:

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 baseline-corrected 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 baseline-corrected 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.

Study in Patients with Established Hypoparathyroidism

The efficacy of Natpara was evaluated in a 24-week, randomized, double-blind, placebo-controlled, multicenter trial. In this trial, patients with established hypoparathyroidism receiving calcium and active forms of vitamin D (vitamin D metabolite or analogs) were randomized (2:1) to Natpara (n=84) or placebo (n=40). The mean age was 47 years (range, 19 to 74 years), 79.0% were females and 96.0% were Caucasian, 0.8% were Black, and 1.6% were Asian. Patients had hypoparathyroidism for on average 15 years and hypoparathyroidism was caused by post-surgical complications in 71% of cases, idiopathic hypoparathyroidism in 25%, DiGeorge Syndrome in 3%, and auto-immune hypoparathyroidism in 1%. Patients with hypoparathyroidism due to calcium-sensing receptor mutations were excluded from the trial. 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.

Before randomization, participants entered a 2-16 weeks run-in phase. In this phase calcium supplement and active vitamin D doses were adjusted to target an albumin-corrected serum calcium concentration between 8.0 and 9.0 mg/dL and 25-hydroxyvitamin D was replaced in patients with insufficient stores. At randomization, baseline serum calcium was 8.6 mg and 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 mcg (0.5, 1) of calcitriol.

At randomization, active forms of vitamin D were reduced by 50% and patients were randomized to Natpara 50 mcg daily or placebo. Randomization was followed by a 12-week Natpara titration phase and a 12-week Natpara dose maintenance phase. During the titration phase Natpara was increased by 25 mcg increments every four weeks up to a maximum of 100 mcg. Titration was indicated for patients who could not achieve independence from active vitamin D and who could not reduce oral calcium to 500 mg or less per day. At end of treatment, 56% of subjects randomized to Natpara were receiving 100 mcg of Natpara per day, 26% were receiving 75 mcg of Natpara per day, and 18% were receiving 50 mcg of Natpara per day. Doses of co-administered active forms of vitamin D and calcium were adjusted (reduced or increased) to maintain albumin-corrected serum calcium within a desired target range throughout the trial in both arms.

For the efficacy analysis, subjects that fulfilled three components of a three-part response criterion were considered responders. A responder was defined as an individual who had: at least a 50% reduction from baseline in the dose of active vitamin D, at least a 50% reduction from baseline in the dose of oral calcium supplementation and an albumin-corrected total serum calcium concentration between 7.5 mg/dL and 10.6 mg/dL.

At the end of treatment, significantly (p-value <0.001) more subjects treated with Natpara [46/84 (54.8%)] compared to placebo [1/40 (2.5%)] met the response criterion. Forty-two percent (35/84) of subjects randomized to Natpara were independent of active forms of vitamin D and were on no more than 500 mg of oral calcium, compared with 2.5% (1/40) of subjects randomized to placebo (p<0.001). There were no differences in the proportion of patients with a calcium level between 7.5 mg and 10.6 mg at end of treatment between subjects randomized to Natpara and placebo.

Table 4 shows the proportion of individuals who, at the end of treatment, fulfilled the 3-part response criterion. Table 5 provides results on individual components of the response criterion.

NDC 68875-0204-2
For subcutaneous use only

Natpara®
(parathyroid hormone)
for Injection

75
mcg/dose

Contains two 14-dose medication
cartridges of Natpara®
(parathyroid hormone) for Injection

Use only after training by a
healthcare provider

• For use with the Mixing Device,
  Q-Cliq™ pen, and 31G x 8 mm
  BD Ultra-Fine™ Pen Needles
• See enclosed Full Prescribing
  Information, Medication Guide,
  and Instructions for Use
• Protect from light
• Do not shake or freeze
• Must be refrigerated.
  Store at 36 to 46°F (2 to 8°C)
• Discard mixed solution after 14 days

Rx only

Shire

Applies to parathyroid hormone: subcutaneous powder for solution

Along with its needed effects, parathyroid hormone (the active ingredient contained in Natpara) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking parathyroid hormone:

• Abdominal or stomach cramps or pain
• blurred vision
• confusion
• constipation
• convulsions
• depression
• difficulty with breathing
• dizziness
• dry mouth
• headache
• incoherent speech
• increased urination
• irregular heartbeats
• loss of appetite
• metallic taste
• muscle cramps in the hands, arms, feet, legs, or face
• muscle weakness
• nausea
• nervousness
• numbness and tingling around the mouth, fingertips, or feet
• pounding in the ears
• slow or fast heartbeat
• thirst
• tremor
• unusual tiredness
• vomiting
• weight loss

Some side effects of parathyroid hormone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abnormal or decreased touch sensation
• body aches or pain
• chills
• cough
• diarrhea
• difficulty with moving
• ear congestion
• fever
• loss of voice
• muscle pain or stiffness
• pain in the joints or neck
• pain or tenderness around the eyes and cheekbones
• sneezing
• sore throat
• stuffy or runny nose
• tightness of the chest
• upper abdominal or stomach pain

Applies to parathyroid hormone: subcutaneous powder for injection

Cardiovascular

Common (1% to 10%): Hypertension[Ref]

Gastrointestinal

Common (1% to 10%): Immunogenicity[Ref]

Genitourinary

Common (1% to 10%): Blood 25-hydroxycholecalciferol decreased[Ref]

Immunologic

Common (1% to 10%): Immunogenicity[Ref]

Metabolic

Very common (10% or more): Hypocalcemia (27%), hypercalcemia (19%)[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (11%), pain in extremity (10%)
Common (1% to 10%): Neck pain[Ref]

Nervous system

Very common (10% or more): Paresthesia (31%), headache (25%), hypoesthesia (14%)
Common (1% to 10%): Facial hypoesthesia[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, sinusitis[Ref]

Some side effects of Natpara may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.