Cinacalcet (Page 2 of 6)

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.

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 [see Adverse Reactions (6.1)] 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 could not be completely excluded and which may be mediated by reductions in serum calcium levels [see Adverse Reactions (6.2)].

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 for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with cinacalcet. 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 and/or vitamin D sterols should be reduced or therapy discontinued.

6 ADVERSE 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)]

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, 1,126 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

Event*:	Placebo (n = 470) (%)	Cinacalcet (n = 656) (%)
Nausea Vomiting Diarrhea Myalgia Dizziness Hypertension Asthenia Anorexia Pain Chest, Non-Cardiac Dialysis Access Site Infection	19 15 20 14 8 5 4 4 44	31 27 21 15 10 77 6 6 5

*Included are events that were reported at a greater incidence in the cinacalcet group than in the placebo group.

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 Study¹

	Placebo (n=1923)	Cinacalcet (n=1938)
	3,699 subject-years	4,044 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

¹ 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.

Additional adverse reaction rates from the long-term, randomized, double-blind placebo-controlled study for cinacalcet 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 in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with cinacalcet 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 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.

Table 3. Adverse Reactions with Frequency ≥ 10% in a Single-Arm, Open-Label Study in Patients with Primary Hyperparathyroidism or Parathyroid Carcinoma

	Cinacalcet
	Parathyroid Carcinoma (n=29) n(%)	Intractable pHPT (n=17) n(%)	Total (n=46) n(%)
Number of Subjects Reporting Adverse Reactions	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)

n=Number of subjects receiving at least one dose of study drug.

pHPT=primary hyperparathyroidism.

In a randomized double-blind, placebo-controlled study of 67 patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo surgery, the most common adverse reactions are listed in Table 4.

Table 4. Adverse Reactions Occurring in ≥ 10% of Subjects in a Double-Blind, Placebo-Controlled Study in Patients with Primary Hyperparathyroidism

Adverse Reaction	Placebo (n = 34) n (%)	Cinacalcet (n = 33) n (%)
Nausea	6 (18)	10 (30)
Muscle spasms	0 (0)	6 (18)
Headache	2 (6)	4 (12)
Back pain	2 (6)	4 (12)

n = Number of subjects receiving at least one dose of study drug Coded using MedDRA version 16.0.

Hypocalcemia

In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving cinacalcet 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 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 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 and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia.

During a placebo-controlled part of a 52-week study in patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dL [2.82 mmol/L] and ≤ 12.5 mg/dL [3.12 mmol/L]), serum calcium less than 8.4 mg/dL was observed in 6.1% (2/33) of cinacalcet-treated patients and 0% (0/34) of placebo-treated patients.