CINACALCET 90 mg ASCEND

Indications

• Secondary hyperparathyroidism in patients with end-stage renal disease on dialysis
• Primary hyperparathyroidism in patients where parathyroidectomy is inappropriate
• Hypercalcemia in parathyroid carcinoma

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Initially 30 mg once daily, adjusted every 2-4 weeks according to response, with a maximum of 180 mg per day. For secondary hyperparathyroidism, initially 30 mg twice daily (maximum 90 mg per dose, up to 4 times a day).

Mechanism of action

Cinacalcet enhances the sensitivity of the calcium-sensing receptor (CaR) to extracellular calcium, promoting the inhibition of parathyroid hormone (PTH) secretion. This results in lower serum calcium levels and addresses the complications associated with elevated PTH in conditions such as chronic kidney disease.

Pharmacodynamics

Cinacalcet acts as a calcimimetic, mimicking the action of calcium on tissues. It is particularly effective in reducing levels of PTH, calcium, and phosphorus in patients with secondary hyperparathyroidism, thus preventing progressive bone disease and other systemic consequences of disordered mineral metabolism. In patients with chronic kidney disease, cinacalcet has been shown to positively impact bone turnover and reduce bone fibrosis.

Pharmacokinetics

Cinacalcet is administered orally, with its bioavailability affected by food intake. It has a volume of distribution that indicates extensive tissue binding. The drug is extensively metabolized by the liver, primarily via CYP2D6 and CYP3A4 pathways, and has a half-life that allows for once or twice daily dosing. Renal impairment does not significantly affect its clearance, but caution is advised in patients with hepatic dysfunction.

Adverse effects

• Hypocalcaemia
• Dizziness
• Nausea
• Vomiting
• Diarrhea
• Headache
• Fatigue
• Seizures

Interactions

• cinacalcet+galantamine: Moderate (increases exposure)
• cinacalcet+risperidone: Moderate (increases exposure)
• cinacalcet+atomoxetine: Moderate (increases exposure)
• cinacalcet+anticholinesterases,centrallyacting: Moderate (increases exposure)
• cobicistat+cinacalcet: Moderate (increases exposure)
• cinacalcet+eliglustat: Moderate (increases exposure)
• cinacalcet+fesoterodine: Moderate (increases exposure)
• idelalisib+cinacalcet: Moderate (increases exposure)
• mitotane+cinacalcet: Moderate (decreases exposure)
• cinacalcet+pitolisant: Moderate (increases exposure)

Precautions

• Monitor serum calcium concentrations before initiation and during treatment.
• Caution in patients with conditions that may worsen with decreased serum calcium.
• Advise patients on symptoms of hypocalcaemia.
• Ensure close monitoring in patients switching from etelcalcetide.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether cinacalcet is excreted in human milk. Caution should be exercised when administering to nursing women.

Storage

Store at room temperature, away from excess moisture and heat. Keep out of reach of children.

Formulations

• {'formulation': 'Granules in capsules for opening', 'strength': '1 mg'}
• {'formulation': 'Granules in capsules for opening', 'strength': '2.5 mg'}
• {'formulation': 'Granules in capsules for opening', 'strength': '5 mg'}

Mechanism of action

Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. Calcimimetics are positive allosteric modulators that activate the parathyroid calcium receptor (CaR) and thereby immediately suppress parathyroid hormone (PTH) secretion. Preclinical studies have demonstrated that calcimimetics inhibit PTH secretion and parathyroid gland hyperplasia and ameliorates bone qualities in rats with chronic renal insufficiency. Clinical trials with cinacalcet hydrochloride, a calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum phosphorus levels in dialysis patients with secondary hyperparathyroidism (2HPT). Thus, calcimimetics have considerable potential as an innovative medical approach to manage 2HPT. In this review, the similarities are extrapolated between the pharmacological effect of calcimimetics on the set point of Ca-regulated PTH secretion and clinical observations in affected subjects with activating CaR mutations. Cinacalcet is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in PTH levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity, resulting in cortical bone resorption and bone marrow fibrosis. The goals of treatment of secondary HPT are to lower levels of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone specific alkaline phosphatase, bone turnover, and bone fibrosis. The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet directly lowers PTH levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. Oral cinacalcet hydrochloride (HCl) is the first in a new class of therapeutic agents, the calcimimetics, and has a novel mechanism of action. It directly modulates the principal regulator of parathyroid hormone (PTH) secretion, namely the calcium-sensing receptor (CaR) on the chief cells in the parathyroid gland. Cinacalcet HCl reduces circulating PTH levels by increasing the sensitivity of the CaR to extracellular calcium. In three pivotal phase III, 26-week, randomised, double-blind, multicentre trials in chronic kidney disease (CKD) patients (n = 1136) on dialysis with uncontrolled secondary hyperparathyroidism (HPT), a significantly higher proportion of oral cinacalcet HCl 30-180 mg/day than placebo recipients achieved a reduction in intact PTH levels to < or =250 pg/mL. Cinacalcet HCl treatment also simultaneously lowered serum calcium and phosphorus, and calcium-phosphorous product levels. Notably, cinacalcet HCl proved effective in a broad range of CKD patients on dialysis with uncontrolled secondary HPT, regardless of disease severity, duration of dialysis treatment, dialysis modality, race, age, gender, or concurrent phosphate binder or vitamin D sterol use. Cinacalcet HCl (60-360 mg/day) also reduced elevated serum calcium levels by > or =1 mg/dL in 15 of 21 (71%) patients with parathyroid carcinoma in an open-label, multicentre, dose-titration trial. Cinacalcet HCl was generally well tolerated in clinical trials. Most treatment-emergent adverse events were mild to moderate in severity. /Cinacalcet hydrochloride/

Pharmacodynamics

Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues). Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium.