Usage
Cinacalcet is prescribed for the following medical conditions:
- Secondary Hyperparathyroidism (HPT) in patients with Chronic Kidney Disease (CKD) on dialysis: Cinacalcet helps control elevated parathyroid hormone (PTH), calcium, and phosphorus levels in these patients.
- Hypercalcemia in patients with Parathyroid Carcinoma: It is used to lower excessively high calcium levels in individuals with this type of cancer.
- Primary Hyperparathyroidism (HPT) in adults: In cases where surgical removal of the parathyroid gland (parathyroidectomy) is not feasible, cinacalcet can be used to manage high calcium levels, especially when clinically significant.
Pharmacological Classification: Calcimimetic
Mechanism of Action: Cinacalcet directly acts on the calcium-sensing receptor (CaSR) on the parathyroid gland. By increasing the sensitivity of the CaSR to calcium, it mimics the effects of higher calcium levels. This leads to a reduction in PTH secretion, which in turn lowers calcium levels in the blood.
Alternate Names
Generic Name: Cinacalcet Hydrochloride
Brand Names: Sensipar, Mimpara (and other regional variations)
How It Works
Pharmacodynamics: Cinacalcet allosterically activates the calcium-sensing receptor (CaSR) in the parathyroid gland, mimicking the effects of extracellular calcium. This increased sensitivity suppresses PTH secretion, leading to decreased serum calcium and phosphorus levels.
Pharmacokinetics:
- Absorption: Cinacalcet is readily absorbed orally, reaching peak plasma concentrations within 2 to 6 hours. Food enhances absorption.
- Metabolism: Primarily metabolized in the liver by CYP450 enzymes, mainly CYP3A4 and CYP1A2.
- Elimination: Cinacalcet has a terminal half-life of 30–40 hours. It is primarily eliminated through hepatic metabolism with a small portion excreted renally. Steady-state is achieved within 7 days with once-daily dosing and within 2-5 days for twice daily administration.
Mode of Action: Cinacalcet is a type II calcimimetic. It binds to the transmembrane CaSR and acts as a positive allosteric modulator. It increases the receptor’s sensitivity to extracellular calcium, which increases its activation. It has no direct effect on calcium levels. It has a greater effect in patients with increased baseline plasma PTH levels.
Receptor Binding: Cinacalcet binds allosterically to the CaSR, distinct from the calcium-binding site.
Enzyme Inhibition/Neurotransmitter Modulation: Not a primary mechanism of action. However, metabolism is primarily mediated by CYP3A4 and CYP1A2.
Elimination Pathways: Primarily hepatic metabolism followed by biliary/fecal excretion. A minor portion is excreted renally.
Dosage
Standard Dosage
Adults:
- Secondary HPT (CKD on dialysis): Initial dose is 30 mg orally once daily, taken with food. Titrate every 2–4 weeks (through sequential doses of 30, 60, 90, 120, and 180 mg once daily) to achieve a target iPTH of 150–300 pg/mL. Maximum dose 180 mg/day in clinical trials.
- Parathyroid Carcinoma and Primary HPT: Initial dose is 30 mg orally twice daily, taken with food. Titrate every 2–4 weeks (through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and up to 90 mg three or four times daily) to normalize serum calcium. Maximum dose used in clinical trials was 90 mg four times daily.
Children:
- Secondary HPT (CKD on dialysis): For children 3 years and older, the initial dose is no more than 0.20 mg/kg of body weight once daily, taken with food. Cinacalcet is available as film-coated tablets. Liquid preparations may exist or compounding may be possible for pediatric administration in case standard tablets are unsuitable. Dosage recommendations are provided by multiple sources, that don’t overlap fully. Refer to pediatric dosage guidelines for specific clinical settings.
- Parathyroid Carcinoma and Primary HPT: Not indicated for children under 18 years of age.
Special Cases:
- Elderly Patients: No dose adjustment is required based on age.
- Patients with Renal Impairment: No dose adjustment necessary.
- Patients with Hepatic Dysfunction: Moderate to severe hepatic impairment increases cinacalcet exposure. Close monitoring of PTH and serum calcium is required during dose titration and ongoing treatment. Consider a lower starting dose.
- Patients with Comorbid Conditions: Monitor closely for hypocalcemia and adjust dose as needed, particularly in patients with a history of seizures, heart failure, or QT interval prolongation.
Clinical Use Cases
Cinacalcet’s use is primarily focused on chronic management of hyperparathyroidism and hypercalcemia, rather than acute settings like intubation, surgery, mechanical ventilation, or ICU or emergency situations. It is not typically used in these contexts.
Dosage Adjustments
Dose titration is based on serum calcium and iPTH levels. Titration should occur no more frequently than every 2-4 weeks. Monitor serum calcium within one week of starting or adjusting the dose. Monitor iPTH 1-4 weeks after initiation or dose adjustment. Once the maintenance dose is stable, monitor calcium monthly in secondary HPT and every 2-3 months in parathyroid carcinoma or primary HPT.
Side Effects
Common Side Effects:
- Nausea
- Vomiting
- Diarrhea
- Dizziness
- Headache
- Muscle pain or cramps
- Asthenia (weakness)
Rare but Serious Side Effects:
- Hypocalcemia (low calcium): This can manifest as muscle spasms, twitching, numbness, tingling, seizures, confusion, or loss of consciousness.
- Seizures (fits or convulsions)
- Worsening of heart failure
- Severe allergic reactions
- QT prolongation and ventricular arrhythmia
Long-Term Effects
- Adynamic bone disease: If PTH levels are suppressed too much, the risk of adynamic bone disease increases.
Adverse Drug Reactions (ADR)
- Hypotension: Isolated, idiosyncratic occurrences of hypotension have been reported.
- Cardiac Arrhythmias: QT prolongation and torsades de pointes (a potentially fatal heart rhythm) have been observed in association with severe hypocalcemia.
Contraindications
- Hypocalcemia: Cinacalcet should not be started if serum calcium is below the lower limit of normal.
- Hypersensitivity: Known hypersensitivity to cinacalcet or any components of the formulation.
Drug Interactions
- CYP3A4 and CYP1A2 Inhibitors/Inducers: Concomitant use with strong CYP3A4 or CYP1A2 inhibitors (e.g., ketoconazole, erythromycin) can increase cinacalcet levels. Inducers (e.g., rifampin) can decrease levels.
- Etelcalcetide: Co-administration is contraindicated.
- Other Medications: Cinacalcet can interact with numerous medications, including those that affect calcium levels (e.g., calcium supplements, vitamin D), those metabolized by CYP3A4 or CYP1A2 (e.g., some statins), and those affecting the QT interval (e.g., some antiarrhythmics).
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Category C (US FDA). Adequate and well-controlled studies in pregnant women are lacking. Cinacalcet should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. Animal data does not indicate an increased risk of teratogenicity with the exception of possible effects related to the drug’s pharmacological mechanism of action.
- Breastfeeding: It is unknown if cinacalcet is excreted in human milk. Due to the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
Drug Profile Summary
- Mechanism of Action: Calcimimetic; allosterically activates the calcium-sensing receptor (CaSR) on the parathyroid gland, suppressing PTH secretion and reducing serum calcium levels.
- Side Effects: Nausea, vomiting, diarrhea, dizziness, hypocalcemia, seizures.
- Contraindications: Hypocalcemia, hypersensitivity.
- Drug Interactions: CYP3A4/1A2 inhibitors/inducers, etelcalcetide, medications affecting calcium/QT interval.
- Pregnancy & Breastfeeding: Use with caution; potential risks to fetus/infant.
- Dosage: See detailed dosage guidelines above.
- Monitoring Parameters: Serum calcium, phosphorus, iPTH, magnesium, potassium, ECG (in patients at risk for QT prolongation).
Popular Combinations
Cinacalcet is often used in combination with phosphate binders and/or vitamin D sterols in patients with secondary HPT on dialysis. This helps optimize management of mineral metabolism in CKD.
Precautions
- General Precautions: Monitor for hypocalcemia, especially during dose titration. Assess renal and hepatic function before starting and periodically during therapy.
- Pregnant Women: Use only if clearly needed, with close monitoring.
- Breastfeeding Mothers: Weigh the benefits and risks carefully. Advise caution.
- Children & Elderly: Monitor closely for hypocalcemia and adjust dose as needed.
- Lifestyle Considerations: Smoking can affect drug clearance. Advise patients not to drive or operate machinery if they experience dizziness or seizures.
FAQs
Q1: What is the recommended dosage for Cinacalcet?
A: Refer to the detailed dosage guidelines provided earlier in this document, which cover various patient populations and clinical scenarios.
Q2: What are the most common side effects of Cinacalcet?
A: The most common side effects are nausea, vomiting, diarrhea, and dizziness.
Q3: What is the mechanism of action of Cinacalcet?
A: Cinacalcet allosterically activates the calcium-sensing receptor on the parathyroid gland, suppressing PTH secretion.
Q4: Is Cinacalcet safe during pregnancy?
A: Cinacalcet is a Pregnancy Category C drug. It should only be used if the potential benefit justifies the potential risk to the fetus.
Q5: Can Cinacalcet be used in children?
A: Cinacalcet is approved for use in children aged 3 years and older with secondary HPT undergoing dialysis.
Q6: How should hypocalcemia be managed in patients taking Cinacalcet?
A: If serum calcium falls below 8.4 mg/dL, but remains above 7.5 mg/dL, consider calcium supplements, increasing the dose of calcium-containing phosphate binders and vitamin D sterols, or temporarily withholding cinacalcet. If serum calcium drops below 7.5 mg/dL, or if symptoms of hypocalcemia persist, withhold cinacalcet until serum calcium levels reach 8.0 mg/dL and/or symptoms resolve, then restart at a lower dose.
Q7: What are the key drug interactions with Cinacalcet?
A: Cinacalcet interacts with CYP3A4/1A2 inhibitors and inducers. Concomitant use of etelcalcetide is contraindicated. Other important interactions involve drugs affecting calcium levels or the QT interval.
Q8: Are there any contraindications to Cinacalcet?
A: Cinacalcet is contraindicated in patients with hypocalcemia and hypersensitivity to the drug.
Q9: What monitoring is required for patients on Cinacalcet?
A: Regularly monitor serum calcium, phosphorus, iPTH levels. Also, assess renal and hepatic function, and in some cases, ECG for QT interval.
Q10: What should patients know about lifestyle while taking Cinacalcet?
A: Patients should inform their doctor if they start or stop smoking. Avoid driving or operating machinery if experiencing dizziness or seizures. Advise taking the medication with food.
