Increases the sensitivity of the calcium-sensing receptor on the parathyroid gland thereby, concomitantly lowering parathyroid hormone (PTH), serum calcium, and serum phosphorus levels, preventing progressive bone disease and adverse events associated with mineral metabolism disorders.

Vd: ~1,000 L

Hepatic (extensive) via CYP3A4, 2D6, 1A2; forms inactive metabolites

Urine ~80% (as metabolites); feces ~15%

~2 to 6 hours; increased with food

Terminal: 30 to 40 hours; moderate hepatic impairment: 65 hours; severe hepatic impairment: 84 hours

~93% to 97%

In patients with moderate or severe hepatic impairment, the AUCs were 2.4 and 4.2 times higher, respectively, than in healthy subjects; the half-life is increased to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively.

Hyperparathyroidism, primary: Treatment of hypercalcemia in adults with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy.

Hyperparathyroidism, secondary: Treatment of secondary hyperparathyroidism in adults with chronic kidney disease (CKD) on dialysis.

Parathyroid carcinoma: Treatment of hypercalcemia in adults with parathyroid carcinoma.

Serum calcium less than the lower limit of normal range

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to any component of the formulation

Hyperparathyroidism, primary: Oral: Initial: 30 mg twice daily; increase dose incrementally every 2 to 4 weeks (to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily) as necessary to normalize serum calcium levels.

Hyperparathyroidism, secondary: Oral: Initial: 30 mg once daily; increase dose incrementally every 2 to 4 weeks (to 60 mg once daily, 90 mg once daily, 120 mg once daily, and 180 mg once daily) as necessary to maintain intact parathyroid hormone (iPTH) level between 150 to 300 pg/mL. May be used alone or in combination with vitamin D and/or phosphate binders.

Parathyroid carcinoma: Oral: Initial: 30 mg twice daily; increase dose incrementally every 2 to 4 weeks (to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 to 4 times daily) as necessary to normalize serum calcium levels.

Refer to adult dosing.

No dosage adjustment necessary.

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B or C): There are no specific dosage adjustments provided in the manufacturer's labeling; exposure and half-life of cinacalcet is increased. Dosage adjustments may be necessary based on serum calcium, serum phosphorus, and/or intact parathyroid hormone (iPTH).

Dosage adjustment for hypocalcemia:

If iPTH <150 pg/mL: Reduce dose or discontinue cinacalcet and/or vitamin D.

Hyperparathyroidism, secondary:

If serum calcium >7.5 mg/dL but <8.4 mg/dL or if hypocalcemia symptoms occur: Use calcium-containing phosphate binders and/or vitamin D to raise calcium levels.

If serum calcium <7.5 mg/dL or if hypocalcemia symptoms persist and the dose of vitamin D cannot be increased: Withhold cinacalcet until serum calcium ≥8 mg/dL and/or symptoms of hypocalcemia resolve. Reinitiate cinacalcet at the next lowest dose.

Administer with food or shortly after a meal. Do not chew, crush, or divide tablet; administer whole.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. Monitor therapy

Amphetamines: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amphetamines.Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Avoid combination

CYP2D6 Substrates (High risk with Inhibitors): CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Exceptions: Tamoxifen. Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. OneU.S.manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Etelcalcetide: Cinacalcet may enhance the hypocalcemic effect of Etelcalcetide. Avoid combination

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Monitor therapy

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

Propafenone: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propafenone.Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): Cinacalcet may decrease the serum concentration of Tacrolimus (Systemic).Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Tamsulosin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin.Monitor therapy

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Tricyclic Antidepressants: Cinacalcet may increase the serum concentration of Tricyclic Antidepressants. Management: Seek alternatives when possible. If these combinations are used, monitor closely for increased effects/toxicity and/or elevated serum concentrations (when testing is available) of the tricyclic antidepressant. Consider therapy modification

>10%:

Cardiovascular: Hypotension (12%)

Central nervous system: Paresthesia (14% to 29%), headache (≤21%), fatigue (12% to 21%), depression (10% to 18%)

Endocrine & metabolic: Hypocalcemia (<8.4 mg/dL: 6% to 75%; <7.5 mg/dL: 29% to 33%), dehydration (≤24%), hypercalcemia (12% to 21%), hypoparathyroidism (intact parathyroid hormone <100 pg/mL: ≤11%)

Gastrointestinal: Nausea (30% to 66%), vomiting (26% to 52%), diarrhea (21%), anorexia (6% to 21%), constipation (5% to 18%), abdominal pain (11%)

Hematologic & oncologic: Anemia (6% to 17%)

Neuromuscular & skeletal: Bone fracture (12% to 21%), muscle spasm (11% to 18%), arthralgia (6% to 17%), weakness (5% to 17%), myalgia (15%), back pain (12%), limb pain (10% to 12%)

Respiratory: Dyspnea (13%), cough (12%), upper respiratory tract infection (8% to 12%)

1% to 10%:

Cardiovascular: Hypertension (7%)

Central nervous system: Dizziness (7% to 10%), noncardiac chest pain (6%), seizure (≤3%)

Endocrine & metabolic: Hyperkalemia (8%)

Gastrointestinal: Upper abdominal pain (8%), dyspepsia (7%), decreased appetite (6%)

Hypersensitivity: Hypersensitivity reaction (9%)

Infection: Localized infection (dialysis access site; 5%)

Frequency not defined: Hematologic & oncologic: Upper gastrointestinal hemorrhage

Postmarketing and/or case reports (Limited to important or life-threatening): Adynamic bone disease, angioedema, cardiac arrhythmia, cardiac failure, gastrointestinal hemorrhage, hypotension (idiosyncratic), prolonged Q-T interval on ECG (secondary to hypocalcemia), skin rash, urticaria, ventricular arrhythmia (secondary to hypocalcemia)

Concerns related to adverse effects:

• Adynamic bone disease: May develop if intact parathyroid hormone (iPTH) levels are suppressed <100 pg/mL; reduce dose or discontinue use of cinacalcet and/or vitamin D if iPTH levels decrease below 150 pg/mL.

• Cardiovascular effects: QT prolongation and ventricular arrhythmia secondary to hypocalcemia may occur. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk. Closely monitor corrected serum calcium and QT interval. Cases of idiosyncratic hypotension, worsening of heart failure, and/or arrhythmia have been reported in patients with impaired cardiovascular function; may correlate with decreased serum calcium.

• GI effects: GI bleeding, mostly upper GI bleeding, have been reported (exact cause unknown); patients with risk factors for upper GI bleeding (eg, gastritis, esophagitis, ulcers, severe vomiting) may be at increased risk. Monitor for worsening of common GI adverse reactions of nausea and vomiting and for signs and symptoms of GI bleeding and ulcerations during therapy.

• Hypocalcemia: Life-threatening and fatal events associated with hypocalcemia have occurred. Monitor serum calcium and for symptoms of hypocalcemia (eg, muscle spasms, myalgia, paresthesia, seizure, tetany). Use with caution in patients receiving concomitant therapies known to lower serum calcium concentrations. May require treatment interruption, dose reduction, or initiation (or dose increases) of calcium-based phosphate binder and/or vitamin D to raise serum calcium depending on calcium levels or symptoms of hypocalcemia. Do not initiate therapy if the corrected serum calcium is less than the lower limit of normal; corrected serum calcium must be at or above the lower limit of normal prior to initiation, dose increase, or reinitiation.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with moderate-to-severe hepatic impairment (Child-Pugh classes B and C); cinacalcet exposure and half-life are increased; monitor serum calcium, serum phosphorus and iPTH closely.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; seizure threshold is lowered by significant serum calcium reductions. Monitor calcium levels closely.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Not indicated for chronic kidney disease (CKD) patients not receiving dialysis. In theUS, the long-term safety and efficacy of cinacalcet has not been evaluated in CKD patients with hyperparathyroidism not requiring dialysis. Although possibly related to lower baseline calcium levels, clinical studies have shown an increased incidence of hypocalcemia (<8.4 mg/dL) in patients not requiring dialysis.

Monitor for signs/symptoms of hypocalcemia. Monitor serum calcium and iPTH concentrations closely in patients on concurrent CYP3A4 inhibitors or with seizure disorders; monitor serum calcium, iPTH, and serum phosphorous concentrations closely in patients with hepatic moderate to severe hepatic impairment.

Hyperparathyroidism, secondary: Serum calcium and phosphorus levels prior to initiation and within a week of initiation and frequently during dose titration; iPTH should be measured 1 to 4 weeks after initiation or dosage adjustment (wait at least 12 hours after dose before drawing iPTH levels). After the maintenance dose is established, obtain serum calcium levels monthly.

Parathyroid carcinoma and hyperparathyroidism, primary: Serum calcium levels prior to initiation and within a week of initiation or dosage adjustment; once maintenance dose is established, obtain serum calcium every 2 months.

Information related to the use of cinacalcet in pregnant women is limited (Edling 2014; Horius 2009; Nadarasa 2014; Rey 2016; Vera 2016).

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, abdominal pain, diarrhea, cough, common cold symptoms, or lack of appetite. Have patient report immediately to prescriber signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of dehydration (dry skin, dry mouth, dry eyes, increased thirst, tachycardia, dizziness, fast breathing, or confusion), signs of bowel bleeding (black, tarry, or bloody stools; vomiting blood; severe abdominal pain; severe nausea; or vomiting), angina, depression, joint pain, muscle pain, severe headache, severe dizziness, passing out, vision changes, shortness of breath, nausea, vomiting, excessive weight gain, swelling of arms or legs, bone pain, or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.