cinacalcet (Rx)

>10%

Secondary Parathyroidism

• Diarrhea (20%)
• Nausea (19%)
• Vomiting (15%)
• Myalgia (14%)

1-10%

Secondary Parathyroidism

• Dizziness (8%)
• Hypertension (5%)
• Access infection (4%)
• Anorexia (4%)
• Asthenia (4%)
• Noncardiac chest pain (4%)
• Seizures 1.4%

Frequency Not Defined

Parathyroid CA

• Nausea/vomiting
• Hypocalcemia

Postmarketing Reports

Hypotension

Worsening heart failure and/or arrhythmias

Adynamic bone disease

Gastrointestinal bleeding

Chondrocalcinosis pyrophosphate (acute pseudogout)

Contraindications

Hypersensitivity

Serum calcium less than lower limit of normal range

Cautions

History of seizure; seizures (primarily generalized or tonic-clonic) were observed in clinical trials (1.4% compared with 0.7% in placebo)

Not for therapy of patients with chronic kidney disease not on dialysis due to increased risk for hypokalemia

Drug exposure is increased in patients with moderate and severe hepatic impairment; monitor serum calcium, serum phosphorus, and intact parathyroid hormone closely

Adynamic bone disease may develop; if iPTH levels decrease below 150 pg/mL in patients receiving therapy, the dose and/or vitamin D sterols should be reduced or therapy discontinued

Therapy is not indicated for patients with CKD not on dialysis ; long-term safety and efficacy of therapy not established in patients with secondary HPT and CKD not on dialysis

Idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia reported in patients with impaired cardiac function, in which a causal relationship to therapy could not be completely excluded and which may be mediated by reductions in serum calcium levels

Significant lowering of calcium by therapy can cause paresthesias, myalgias, muscle spasms, tetany, and seizures; QT interval prolongation and ventricular arrhythmia; life-threatening events and fatal outcomes associated with hypocalcemia reported, including in pediatric patients

Threshold for seizures is lowered by significant reductions in serum calcium levels; monitor serum calcium levels in patients with seizure disorders

Educate patients on symptoms of hypocalcemia and advise them to contact a healthcare provider if they occur; if corrected serum calcium falls below lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols or increases in dialysate calcium concentration)

Gastrointestinal bleeding

• Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, reported in patients using calcimimetics
• The exact cause of GI bleeding is unknown; patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers or severe vomiting) may be at increased risk for GI bleeding when receiving treatment
• Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with therapy and for signs and symptoms of GI bleeding and ulcerations during therapy
• Promptly evaluate and treat any suspected GI bleeding

QT interval prolongation and ventricular arrhythmia

• Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmia; cases of QT prolongation and ventricular arrhythmia reported in patients receiving therapy; 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 increase risk for QT interval prolongation and ventricular arrhythmias
• In patients at risk, receiving therapy, who develop hypocalcemia, closely monitor corrected serum calcium and QT interval

Drug interactions overview

• Concurrent administration with calcium-lowering drugs including other calcium-sensing receptor agonists could result in severe hypocalcemia; closely monitor serum calcium in patients receiving the drug therapy and concomitant therapies known to lower serum calcium levels

Pregnancy

Limited case reports of use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes; in animal reproduction studies, when female rats were exposed to the drug during the period of organogenesis through to weaning at 2-3 times systemic drug levels (based on AUC) at maximum recommended human dose (MRHD) of 180 mg/day, peripartum and early postnatal pup loss and reduced pup body weight gain were observed in the presence of maternal hypocalcemia

Lactation

There are no data regarding presence in human milk or effects on breastfed infant or on milk production; studies in rats showed that cinacalcet was excreted in milk; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Increases sensitivity of Ca-sensing receptor in parathyroid cells to activation by extracellular Ca, thereby downregulating PTH levels and consequently lowering serum Ca & phosphorus

Absorption

Bioavailability: High fat meal increases both peak plasma concentration and AUC vis-a-vis fasting

Peak Plasma Time: 2-6 hr

Distribution

Protein Bound: 93-97%

Vd: 1000 L

Metabolism

Metabolism: metabolized by CYP3A4, CYP2D6 & CYP1A2

Metabolites: hydrocinnamic and hydroxy-hydrocinnamic acid, naphthalene-ring-containing molecules, dihydrodiols

Enzyme Inhibited: CYP2D6

Elimination

Half-Life: 30-40 hr

Excretion: Urine (80%); feces (15%)

Oral Administration

Take with food or shortly after meal

Swallow tablet whole, do not chew, crush, or divide