CINACALCET: 42,711 Adverse Event Reports & Safety Profile

Cinacalcet tablets contain the hydrochloride salt of the active ingredient cinacalcet, a positive modulator of the calcium sensing receptor. Its empirical formula for cinacalcet is C 22 H 22 F 3 N•HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity. The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water. The hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula: Cinacalcet tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).

Inactive Ingredients

The following are the inactive ingredients in cinacalcet tablets: microcrystalline cellulose, crospovidone and magnesium stearate. Tablets are coated with hypromellose, titanium dioxide, triacetin FD&C Blue No 2 and iron oxide yellow. The following structural formula for hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride.

AND USAGE Cinacalcet tablet is a positive modulator of the calcium sensing receptor indicated for:

• Secondary Hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis. ( 1.1 ) Limitations of Use : Cinacalcet tablets are not indicated for use in patients with CKD who are not on dialysis
• Hypercalcemia in adult patients with Parathyroid Carcinoma (PC). ( 1.2 )
• Hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. ( 1.3 )

1.1 Secondary Hyperparathyroidism Cinacalcet tablets are indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> . Limitations of Use: Cinacalcet tablets are not indicated for use in patients with CKD who are not on dialysis because of an increased risk of hypocalcemia <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

1.2 Parathyroid Carcinoma Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> .

1.3 Primary Hyperparathyroidism Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 )]</span> .

AND ADMINISTRATION Cinacalcet hydrochloride tablets should be taken with food or shortly after a meal ( 2.1 ). Tablets should always be taken whole and not divided ( 2.1 ) Secondary HPT in patients with CKD on dialysis ( 2.2 ): Starting dose is 30 mg once daily. Titrate dose no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily as necessary to achieve targeted intact parathyroid hormone (iPTH) levels. iPTH levels should be measured no earlier than 12 hours after most recent dose. Hypercalcemia in patients with PC or severe hypercalcemia in patients with primary HPT ( 2.3 ): Starting dose is 30 mg twice daily. Titrate dose every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalize serum calcium levels. Once the maintenance dose has been established, monitor serum calcium approximately monthly for patients with secondary HPT and every 2 months for patients with PC or primary HPT ( 2.4 )

2.1 Administration Cinacalcet hydrochloride tablets should be taken with food or shortly after a meal. Cinacalcet hydrochloride tablets are administered orally and should always be taken whole and not chewed, crushed, or divided.

2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis The recommended starting oral dose of cinacalcet hydrochloride tablets is 30 mg once daily. Serum calcium and serum phosphorus should be measured within 1 week and intact parathyroid hormone (iPTH) should be measured 1 to 4 weeks after initiation or dose adjustment of cinacalcet hydrochloride tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . Cinacalcet hydrochloride tablets should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily to target iPTH levels of 150 to 300 pg/mL. Serum iPTH levels should be assessed no earlier than 12 hours after dosing with cinacalcet hydrochloride tablets. Cinacalcet hydrochloride tablets can be used alone or in combination with vitamin D sterols and/or phosphate binders. During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with cinacalcet hydrochloride tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )]</span> .

2.3 Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism The recommended starting oral dose of cinacalcet hydrochloride tablet is 30 mg twice daily. The dose of cinacalcet hydrochloride tablets should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels. Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet hydrochloride tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )]</span>.

2.4 Switching from Parsabiv (etelcalcetide) to Cinacalcet Discontinue etelcalcetide for at least 4 weeks prior to starting Cinacalcet. Ensure corrected serum calcium is at or above the lower limit of normal prior to Cinacalcet initiation <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> .

Initiate

Cinacalcet treatment at a starting dose of 30 mg once daily.

2.5 Monitoring for Hypocalcemia Once the maintenance dose has been established, serum calcium should be measured approximately monthly for patients with secondary hyperparathyroidism with CKD on dialysis, and every 2 months for patients with parathyroid carcinoma or primary hyperparathyroidism <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 , 2.3 )]</span> . For secondary hyperparathyroidism patients with CKD on dialysis, if serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of cinacalcet hydrochloride tablets until serum calcium levels reach 8.0 mg/dL and/or symptoms of hypocalcemia have resolved. Treatment should be reinitiated using the next lowest dose of cinacalcet hydrochloride tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</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 )

REACTIONS The following adverse reactions are discussed in greater detail in other sections of labeling: Hypocalcemia [see Warnings and Precautions ( 5.1 )]

Upper Gastrointestinal

Bleeding [see Warnings and Precautions ( 5.2 )] Hypotension, Worsening Heart Failure and/or Arrhythmias [ see Warnings and Precautions ( 5.3 )]

Adynamic Bone

Disease [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (i.e., ≥ 25%) associated with cinacalcet hydrochloride were nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, Exelan Pharmaceuticals, Inc ., at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Secondary

Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 cinacalcet, 470 placebo) for up to 6 months. The most frequently reported adverse reactions are listed in Table 1. Seizures were observed in 1.4% (13/910) of cinacalcet-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo-controlled trials.

Table

1.

Adverse

Reactions with Frequency ≥ 5% in Patients on Dialysis in Short-Term Studies for up to 6 Months Placebo (n = 470) Cinacalcet (n = 656)

Event

Included are events that were reported at a greater incidence in the cinacalcet group than in the placebo group (%) (%)

Nausea

19 31 Vomiting 15 27 Diarrhea 20 21 Myalgia 14 15 Dizziness 8 10 Hypertension 5 7 Asthenia 4 7 Anorexia 4 6 Pain Chest, Non-Cardiac 4 6 Dialysis Access Site Infection 4 5 In a randomized, double-blind placebo-controlled study of 3-883 patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the cinacalcet group), the most frequently reported adverse reactions (incidence of ≥ 5% in the cinacalcet group and a difference ≥ 1% compared to placebo) are listed in Table 2.

Table

2. Frequency of Adverse Reactions in Dialysis Patients Treated for up to 64 Months in a Long-Term Study Adverse reactions that occurred in ≥ 5% frequency in the cinacalcet group and a difference ≥1% compared to the placebo group (Safety Analysis Set) Crude incidence rate = 100 * Total number of subjects with event/ n n=Number of subjects receiving at least one dose of study drug Placebo (n=1923) Cinacalcet (n=1938) 3699 subject-years 4044 subject-years Percent of subjects reporting Adverse Reactions (%) 90.9

93.2 Nausea 15.5

29.1 Vomiting 13.7

25.6 Diarrhea 18.7

20.5 Dyspnea 11.5

13.4 Cough 9.8

11.7 Hypotension 10.5

11.6 Headache 9.6

11.5 Hypocalcemia 1.4

11.2 Muscle spasms 9.2

11.1 Abdominal pain 9.6

10.9 Abdominal pain upper 6.3

8.2 Hyperkalemia 6.1

8.1 Upper respiratory tract infection 6.3

7.6 Dyspepsia 4.6

7.4 Dizziness 4.7

7.3 Decreased appetite 3.5

5.9 Asthenia 3.8

5.4 Constipation 3.8

5.0 Additional adverse reaction rates from the long-term, randomized, double-blind placebo-controlled study for cinacalcet tablets versus placebo are as follows: seizure (2.5%, 1.6%), rash (2.2%, 1.9%), hypersensitivity reactions (9.4%, 8.3%). Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism The safety profile of cinacalcet hydrochloride tablets in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with cinacalcet hydrochloride tablets in a single-arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms. Eight patients died during treatment with cinacalcet hydrochloride tablets in this study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT. Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage (1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in three patients (7%). Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies.

Hypocalcemia In

26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving cinacalcet hydrochloride tablets compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29% of patients receiving cinacalcet hydrochloride tablets compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia. In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the cinacalcet group), 75% of patients receiving cinacalcet hydrochloride tablets compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL. Most of the cases of severe hypocalcemia less than 7.5 mg/dL (21/33=64%) occurred during the first 6 months. In this trial, 1.1% of patients receiving cinacalcet hydrochloride tablets and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia.

Table

3.

Adverse

Reactions with Frequency ≥ 10% in a Single-Arm, Open-Label Study in Patients with Primary Hyperparathyroidism or Parathyroid Carcinoma n=Number of subjects receiving at least one dose of study drug. pHPT=primary hyperparathyroidism Cinacalcet Hydrochloride Tablets Parathyroid Carcinoma (n=29) n (%) Intractable pHPT (n=17) n (%) Total (n=46) n (%) Number of Subjects Reporting Adverse Reaction 28 (97) 17 (100) 45 (98)

Nausea

19 (66) 10 (59) 29 (63)

Vomiting

15 (52) 6 (35) 21 (46)

Paresthesia

4 (14) 5 (29) 9 (20)

Fatigue

6 (21) 2 (12) 8 (17)

Fracture

6 (21) 2 (12) 8 (17)

Hypercalcemia

6 (21) 2 (12) 8 (17)

Anorexia

6 (21) 1 (6) 7 (15)

Asthenia

5 (17) 2 (12) 7 (15)

Dehydration

7 (24) 0 (0) 7 (15)

Anemia

5 (17) 1 (6) 6 (13)

Arthralgia

5 (17) 1 (6) 6 (13)

Constipation

3 (10) 3 (18) 6 (13)

Depression

3 (10) 3 (18) 6 (13)

Headache

6 (21) 0 (0) 6 (13)

Infection Upper Respiratory

3 (10) 2 (12) 5 (11)

Pain Limb

3 (10) 2 (12) 5 (11)

Hypocalcemia In

26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving cinacalcet hydrochloride tablets compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29 % of patients receiving cinacalcet hydrochloride tablets compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia. In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the cinacalcet group), 75% of patients receiving cinacalcet hydrochloride tablets compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL. Most of the cases of severe hypocalcemia less than 7.5mg/dL (21/33=64%) occurred during the first 6 months. In this trial, 1.1% of patients receiving cinacalcet hydrochloride tablets and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of cinacalcet tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Rash and hypersensitivity reactions (including angioedema, and urticaria), and myalgia have been identified as adverse reactions during post approval use of cinacalcet tablets. Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in cinacalcet-treated patients with impaired cardiac function in postmarketing safety surveillance <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span>. Rash and hypersensitivity reactions (including angioedema and urticaria), and myalgia Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function Gastrointestinal bleeding Chondrocalcinosis pyrophosphate (acute pseudogout)

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 &lt; 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.

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> .