Cinacalcet

Cinacalcet directly lowers PTH by increasing the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium. Reduction in PTH is accompanied by a concomitant decrease in serum calcium and, in CKD, in serum phosphorus and calcium-phosphate product.

Mechanism of Action

• Allosteric CaSR activation: cinacalcet binds at an allosteric (Type II calcimimetic) site on the seven-transmembrane CaSR expressed on parathyroid chief cells, lowering the activation threshold of the receptor for extracellular Ca²⁺. The receptor signals more strongly at any given calcium concentration.
• Suppressed PTH secretion: activated CaSR signals via Gq/11 (phospholipase C-β, IP3, intracellular Ca²⁺) and Gi/o (inhibition of cAMP) to inhibit PTH synthesis and release.
• Mineral metabolism: reduction of PTH lowers bone resorption and renal/intestinal calcium reabsorption, decreasing serum calcium and (in CKD) phosphate.
• Favourable bone effects in CKD: reductions in PTH translate to improvements in bone-specific alkaline phosphatase, bone turnover, and reduced marrow fibrosis.

Pharmacokinetics

• Absorption: rapidly absorbed after oral administration. Food markedly increases bioavailability — must be taken with food or shortly after eating.
• Volume of distribution: approximately 1,000 L (extensive tissue distribution).
• Protein binding: 93–97% to plasma proteins.
• Metabolism: extensive hepatic metabolism by CYP3A4, CYP2D6, and CYP1A2 via oxidative N-dealkylation to hydrocinnamic and hydroxy-hydrocinnamic acids and oxidation of the naphthalene ring to dihydrodiols (glucuronidated).
• Half-life: terminal half-life 30–40 hours; prolonged by ~33% in moderate and ~70% in severe hepatic impairment.
• Excretion: predominantly renal excretion of metabolites; minimal unchanged drug recovered.

• Secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease on maintenance dialysis (haemodialysis or peritoneal dialysis).
• Hypercalcaemia in patients with parathyroid carcinoma.
• Severe hypercalcaemia in adult patients with primary hyperparathyroidism (PHPT) for whom parathyroidectomy would be indicated on the basis of serum calcium levels but in whom surgery is not clinically appropriate or is contraindicated.
• Paediatric SHPT on dialysis (≥3 years), in some markets, with stringent calcium monitoring and granule formulations.

• Hypersensitivity to cinacalcet or any excipient.
• Serum calcium below the lower limit of normal — cinacalcet should not be initiated unless corrected calcium is ≥8.4 mg/dL (2.1 mmol/L). In paediatric use, lower thresholds apply per labelling.

Very common (≥1/10): nausea, vomiting, diarrhoea; hypocalcaemia.

Common (≥1/100 to <1/10): anorexia, decreased appetite; dizziness, paraesthesia; headache; hypertension; dyspepsia, abdominal pain (upper), constipation; rash; myalgia; muscle spasms; asthenia, fatigue; back pain; reduced testosterone levels in male haemodialysis patients.

Uncommon (≥1/1,000 to <1/100): seizures (especially in patients with predisposing factors and hypocalcaemia); QT prolongation; hypersensitivity reactions; gastrointestinal haemorrhage (case reports).

Rare (<1/1,000): angioedema; severe hypocalcaemia precipitating arrhythmia in susceptible patients.

Post-marketing (paediatric): fatal cases linked to severe hypocalcaemia — strict serum-calcium monitoring is mandatory before and during therapy.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir): increase cinacalcet exposure; dose adjustment may be required.
• CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John’s wort): may reduce cinacalcet exposure and efficacy.
• CYP2D6 substrates with narrow therapeutic index (flecainide, propafenone, metoprolol, vinblastine, desipramine, tricyclic antidepressants, most opioids): cinacalcet is a strong CYP2D6 inhibitor — substrate dose reduction may be required.
• Vitamin D analogues (calcitriol, paricalcitol, alfacalcidol) and calcium-containing phosphate binders: monitor closely — combined therapy is common in CKD-SHPT and is part of the overall mineral-bone management strategy, but additive hypocalcaemia or hypercalcaemia can occur.
• Etelcalcetide and other calcimimetics: do not co-administer.

Tablets should be taken with food or shortly after a meal, swallowed whole with water — do not chew, crush, or split. Food increases absorption significantly.

Secondary Hyperparathyroidism in Dialysis (Adults)

• Starting dose: 30 mg once daily.
• Titration: every 2–4 weeks based on serum corrected calcium (target ≥8.4 mg/dL / 2.1 mmol/L) and intact PTH (target per local CKD-MBD guidelines, typically 2–9× upper limit of normal).
• Maintenance: typically 30–180 mg once daily; maximum 180 mg/day.
• Monitoring: serum calcium and phosphate within 1 week and PTH within 1–4 weeks of dose changes.

Parathyroid Carcinoma and Primary Hyperparathyroidism

• Starting dose: 30 mg twice daily.
• Titration: every 2–4 weeks (60 mg twice daily, then 90 mg twice daily, then 90 mg three or four times daily) to normalise serum calcium.
• Maximum: 90 mg four times daily.

Renal Impairment

No dose adjustment based on renal function per se; dosing is driven by serum calcium and PTH. Cinacalcet has not been studied in non-dialysis CKD SHPT outside specific paediatric and trial settings.

Hepatic Impairment

No initial dose adjustment in mild hepatic impairment. Use cautiously and monitor closely in moderate to severe hepatic impairment, given prolonged half-life.

Missed Dose

Take as soon as remembered the same day. If close to the next scheduled dose, skip and resume the regular schedule.

Hypocalcaemia

The major dose-limiting effect. Risk is increased by concurrent vitamin D analogue under-dosing, malnutrition, and (in paediatrics) growth. Symptoms include paraesthesia, myalgia, cramps, tetany, convulsions, and QT prolongation. Discontinue or hold for severe hypocalcaemia; supplement calcium and active vitamin D as indicated.

Seizures

Increased seizure risk reported, particularly with rapid drops in serum calcium. Caution in patients with prior seizure history.

Cardiovascular

QT prolongation possible. Caution in patients with congenital long QT syndrome, on QT-prolonging drugs, or with significant electrolyte disturbance.

Adynamic Bone Disease

Sustained over-suppression of PTH (intact PTH <100 pg/mL or <15× upper limit of normal in some guidelines) may worsen adynamic bone disease — review dosing if PTH falls below target.

Pregnancy and Lactation

• Pregnancy: limited human data; animal data show developmental toxicity at maternally toxic doses. Use only if benefit outweighs risk.
• Breastfeeding: passage into breast milk unknown — avoid where possible.

Paediatric

Authorised in some markets for SHPT in dialysis-dependent CKD in children ≥3 years. Risks of severe hypocalcaemia mandate strict monitoring and specialist supervision.

Effect on Driving

Generally not affected; advise caution if dizziness occurs.

This medicinal product does not require any special storage conditions. Keep in the original packaging.

5 years for film-coated tablets. Do not use after the expiry date printed on the packaging.

Prescription required (Rx).