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Cinacalcet

Pronunciation

Pronunciation

(sin a KAL cet)

Index Terms

  • AMG 073
  • Cinacalcet Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Sensipar: 30 mg, 60 mg, 90 mg

Brand Names: U.S.

  • Sensipar

Pharmacologic Category

  • Calcimimetic

Pharmacology

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.

Distribution

Vd: ~1,000 L

Metabolism

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

Excretion

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

Time to Peak

~2 to 6 hours; increased with food

Half-Life Elimination

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

Protein Binding

~93% to 97%

Special Populations: Hepatic Function Impairment

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.

Use: Labeled Indications

Hyperparathyroidism, primary: Treatment of severe hypercalcemia in adult patients 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 adult patients with chronic kidney disease (CKD) on dialysis.

Limitation of use: Not indicated for use in patients with CKD who are not on dialysis (due to the increased risk of hypocalcemia)

Parathyroid carcinoma: Treatment of hypercalcemia in adult patients with parathyroid carcinoma

Contraindications

Serum calcium lower than the lower limit of normal range

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

Dosing: Adult

Note: Do not titrate dose more frequently than every 2 to 4 weeks. May be used alone or in combination with vitamin D and/or phosphate binders. Dosage adjustment may be required in patients on concurrent CYP3A4 inhibitors.

Hyperparathyroidism, primary: Oral: Initial: 30 mg twice daily; increase dose incrementally (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 (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.

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

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

Moderate to severe impairment (Child-Pugh class B or C); may have an increased exposure to cinacalcet and increased half-life. Dosage adjustments may be necessary based on serum calcium, serum phosphorus, and/or iPTH.

Dosing: Adjustment for Toxicity

Dosage adjustment for hypocalcemia:

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.

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

Administration

Administer with food or shortly after a meal. Do not break or divide tablet; should be taken whole.

Storage

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

Drug Interactions

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. 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

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. Avoid combination

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

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

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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. 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. One U.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

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. Monitor therapy

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. 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. 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. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. 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: May increase the serum concentration of CYP2D6 Inhibitors (Moderate). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

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

Adverse Reactions

>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%)

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

Warnings/Precautions

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: 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. QT prolongation and ventricular arrhythmia secondary to hypocalcemia have also been reported.

• Hypocalcemia: Life-threatening and fatal events associated with hypocalcemia have occurred. Use is contraindicated if the serum calcium is less than the lower limit of the normal range. Monitor serum calcium and for symptoms of hypocalcemia (eg, muscle cramps, myalgia, paresthesia, seizure, tetany). 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.

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 the U.S., 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.

Monitoring Parameters

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

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.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Women who become pregnant during cinacalcet treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program (1-800-772-6436).

Patient Education

• 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, diarrhea, or lack of appetite. Have patient report immediately to prescriber signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures), angina, severe nausea, severe vomiting, depression, arrhythmia, joint pain, muscle pain, severe headache, severe dizziness, passing out, shortness of breath, excessive weight gain, swelling of arms of legs, bone pain, thirsty, severe loss of strength and energy, or dry mouth (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.

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