INTERACTIONS Co-administration with a strong CYP3A4 inhibitor may increase serum levels of cinacalcet. Dose adjustment and monitoring of iPTH serum phosphorus and serum calcium may be required. ( 7.1 ) Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6. ( 7.2 )
7.1 Strong CYP3A4 Inhibitors Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of cinacalcet hydrochloride tablets may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .
7.2 CYP2D6 Substrates Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .
Cinacalcet hydrochloride tablets treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range [see Warnings and Precautions ( 5.1 )]. Cinacalcet tablets treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range. ( 4 , 5.1 )
AND PRECAUTIONS Hypocalcemia : Life threatening events and fatal outcomes were reported. Hypocalcemia can prolong QT interval, lower the threshold for seizures, and cause hypotension, worsening heart failure, and/or arrhythmia. Monitor serum calcium carefully for the occurrence of hypocalcemia during treatment ( 2.4 , 5.1 )
Upper
Gastrointestinal (GI) Bleeding: Patients with risk factors for upper GI bleeding may be at increased risk. Monitor patients and promptly evaluate and treat any suspected GI bleeding. ( 5.2 ) Hypotension, Worsening Heart Failure and/or Arrhythmias : In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function. ( 5.3 ) Adynamic B one D isease : May develop if iPTH levels are suppressed below 100 pg/mL. ( 5.4 )
5.1 Hypocalcemia Cinacalcet lowers serum calcium and can lead to hypocalcemia <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. Significant lowering of serum calcium can cause paresthesias, myalgias, muscle spasms, tetany, seizures, QT interval prolongation and ventricular arrhythmia. Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with cinacalcet tablets, including in pediatric patients. The safety and effectiveness of cinacalcet tablets have not been established in pediatric patients <span class="opacity-50 text-xs">[see Pediatric Use ( 8.4 )]</span>. Cinacalcet tablets are not indicated for patients with CKD not on dialysis <span class="opacity-50 text-xs">[see I ndications and Usage ( 1 )]</span> . In patients with secondary HPT and CKD not on dialysis, the long term safety and efficacy of cinacalcet tablets have not been established. Clinical studies indicate that cinacalcet-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with cinacalcet-treated patients with CKD on dialysis, which may be due to lower baseline calcium levels. In a phase 3 study of 32 weeks duration and including 404 patients with CKD not on dialysis (302 cinacalcet, 102 placebo), in which the median dose for cinacalcet was 60 mg per day at the completion of the study, 80% of cinacalcet-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo. QT Interval Prolongation and Ventricular Arrhythmia Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with cinacalcet tablets. 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 for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to cinacalcet tablets. Closely monitor corrected serum calcium and QT interval in patients at risk receiving cinacalcet tablets. Seizures In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of cinacalcet-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Monitor serum calcium levels in patients with seizure disorders receiving cinacalcet tablets . Concurrent administration of cinacalcet tablets with calcium-lowering drugs including other calcium-sensing receptor agonists could result in severe hypocalcemia. Closely monitor serum calcium in patients receiving cinacalcet tablets and concomitant therapies known to lower serum calcium levels. Educate patients on the symptoms of hypocalcemia and advise them to contact a healthcare provider if they occur. If corrected serum calcium falls below the 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). Cinacalcet tablets dose reduction or discontinuation of cinacalcet tablets may be necessary <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>.
5.2 Upper Gastrointestinal Bleeding Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using calcimimetics, including cinacalcet, from postmarketing and clinical trial sources. The exact cause of GI bleeding in these patients is unknown. Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using calcimimetics, including cinacalcet, from postmarketing and clinical trial sources. The exact cause of GI bleeding in these patients 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 cinacalcet treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with cinacalcet and for signs and symptoms of GI bleeding and ulcerations during cinacalcet therapy. Promptly evaluate and treat any suspected GI bleeding. 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 cinacalcet treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with cinacalcet <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> and for signs and symptoms of GI bleeding and ulcerations during cinacalcet therapy. Promptly evaluate and treat any suspected GI bleeding.
5.3 Hypotension, Worsening Heart Failure and/or Arrhythmias In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to cinacalcet tablets could not be completely excluded and which may be mediated by reductions in serum calcium levels <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>.
5.4 Adynamic Bone Disease Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with cinacalcet tablets for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with cinacalcet tablets. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In three 6-month, phase 3 studies conducted in patients with CKD on dialysis, 11% of patients treated with cinacalcet had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below 150 pg/mL in patients treated with cinacalcet, the dose of cinacalcet tablets and/or vitamin D sterols should be reduced or therapy discontinued.