Cinacalcet

Cinacalcet is an Calcium sensing receptor agonist belonging to pharmacology class of Calcimimetic Agent.

Cinacalcet can be used in the treatment of Hyperparathyroidism, primary, Hyperparathyroidism, secondary (dialysis-dependent chronic kidney disease), Conversion from etelcalcetide, Parathyroid carcinoma, hypercalcemia treatment.

Cinacalcet has Increased bioavailability and peak plasma concentrations with food. Absolute bioavailability: Approx 20-25% (fasted state). Time to peak plasma concentration: Approx 2-6 hours and Extensively get distributed in the body. Volume of distribution: Approx 1,000 L. Plasma protein binding: Approx 93-97% and rapidly and extensively get metabolized in the liver primarily by CYP3A4, CYP1A2, and CYP2D6 isoenzymes via oxidative N-dealkylation and oxidation of the naphthalene ring into inactive metabolites and get excreted mainly via urine (approx 80% as metabolites); faeces (approx 15%). Elimination half-life: Approx 6 hours (initial); 30-40 hours (terminal).

Cinacalcet is available in the form of Tablets.

The molecule is available in India, USA, Japan, Germany.

Increases the sensitivity of the calcium-sensing receptor on the parathyroid gland thereby, concomitantly lowering parathyroid hormone (PTH), serum calcium, and serum phosphorus levels, preventing progressive bone disease and adverse events associated with mineral metabolism disorders.

Cinacalcet can be used in the treatment of Hyperparathyroidism, primary, Hyperparathyroidism, secondary (dialysis-dependent chronic kidney disease), Conversion from etelcalcetide, Parathyroid carcinoma, hypercalcemia treatment.

Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary HPT are to lower the levels of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. Reductions in PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.

Hyperparathyroidism, primary: Oral: Initial: 30 mg twice daily; may increase dose incrementally (to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily) every 2 to 4 weeks as necessary to normalize serum calcium levels.

Hyperparathyroidism, secondary (dialysis-dependent chronic kidney disease):

Note: In patients with severely elevated parathyroid hormone (PTH) levels (eg, >800 pg/mL), cinacalcet monotherapy may be inadequate to achieve target PTH levels; combination therapy (eg, with calcitriol or vitamin D analogs and/or phosphate binders) may be required.

Oral: Initial: 30 mg once daily; may increase dose in 30 mg/day increments every 2 to 4 weeks up to 180 mg once daily as necessary to maintain target PTH levels.

Conversion from etelcalcetide : Discontinue etelcalcetide for at least 4 weeks prior to initiating cinacalcet.

Parathyroid carcinoma, hypercalcemia treatment: Oral: Initial: 30 mg twice daily; may increase dose incrementally (to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 to 4 times daily) every 2 to 4 weeks as necessary to normalize serum calcium levels.

Tablets: 30 mg, 60 mg, 90 mg.

Tablets

• Dose Adjustment in Kidney impairment patient:

Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction.

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed: No supplemental dose or dosage adjustment necessary .

Peritoneal dialysis: Not significantly dialyzed: No dosage adjustment necessary.

CRRT: No dosage adjustment necessary.

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary

• Dose Adjustment in Hepatic Patient:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B or C): There are no specific dosage adjustments provided in the manufacturer's labeling; exposure and half-life of cinacalcet is increased. Dosage adjustments may be necessary based on serum calcium, phosphorus, and/or parathyroid hormone levels.

Hyperparathyroidism, secondary: Note: Should only be used when standard therapies have proven ineffective. Ensure calcium is in normal range before initiating therapy and monitor closely throughout treatment. Dosing based on patient's dry weight.

• Dose Adjustment in Pediatric Patient:

Hyperparathyroidism, secondary: Note: Should only be used when standard therapies have proven ineffective. Ensure calcium is in normal range before initiating therapy and monitor closely throughout treatment. Dosing based on patient's dry weight.

Children ≥3 years and Adolescents: Limited data available, optimal dosage not established in pediatric patients: Oral:

Weight-directed dosing: Initial: ≤0.2 mg/kg/dose once daily; may titrate every 4 weeks to reach target range of intact parathyroid hormone (iPTH) of 100 to 300 pg/mL. Maximum daily dose: 180 mg/day or 2.5 mg/kg/dose (whichever is lower). Dosing based on a randomized, double-blind study (n=43) with an open-label phase (n=12) with secondary hyperparathyroidism on hemodialysis or peritoneal dialysis. Cinacalcet was started at ≤0.2 mg/kg/day in 22 patients (mean age: 13.3 ± 3.6 years) and titrated every 4 weeks to goal iPTH. For the efficacy endpoint phase, the mean weight adjusted dose was 1.54 mg/kg/day which corresponded to 50.4 mg/day. iPTH was decreased by ≥30% in 54% of patients receiving cinacalcet compared to 19% with placebo. Serum calcium was significantly reduced in patients receiving cinacalcet compared to placebo and severe hypocalcemia (<7.5 mg/dL) occurred in 3 patients, including 1 death where treatment-related cause could not be ruled out (corrected calcium was 5.3 mg/dL). This study was placed on hold following the reported death and ultimately terminated after 14 months. Despite the limited number of patients enrolled due to study termination, efficacy was still demonstrated.

Note: Cinacalcet use in children <3 years and infants as young as 8 months has been described; however, variable dosing strategies were used or only single doses were administered.

Cinacalcet should be taken with or shortly after food.

Cinacalcet may be contraindicated in the following conditions:

Hypocalcemia

Cinacalcet treatment should not be initiated if serum calcium is less than the lower limit of the normal range.

Precautions

Hypocalcemia

Cinacalcet lowers serum calcium and, therefore, patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesia, myalgias, muscle cramping, tetany, and convulsions.

Serum calcium should be measured within 1 week after initiation or dose adjustment of Cinacalcet . Once the maintenance dose has been established, serum calcium should be measured approximately monthly.

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 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 .

In 26-week studies of patients with CKD on dialysis, 66% of patients receiving Cinacalcet compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.

Cinacalcet is not indicated for patients with CKD not on dialysis. In patients with secondary HPT and CKD not on dialysis, the long term safety and efficacy of Cinacalcet 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 < 8.4 mg/dL compared with 5% of patients receiving placebo.

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. Therefore, serum calcium levels should be closely monitored in patients receiving Cinacalcet , particularly in patients with a history of a seizure disorder.

Hypotension and/or Worsening Heart Failure

In post-marketing 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.

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.

Hepatic Impairment

Cinacalcet exposure, as defined by the Area Under the Curve (AUC0-inf), is increased by 2.4 and 4.2 fold in patients with moderate and severe hepatic impairment, respectively. These patients should be monitored throughout treatment with Cinacalcet .

Laboratory Tests

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Cinacalcet . Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and iPTH every 1 to 3 months. Measurements of PTH during the Cinacalcet studies were obtained using the Nichols iPTH immunoradiometric assay (IRMA).

In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled study in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following 6 months of treatment with Cinacalcet . Levels of total testosterone decreased by a median of 15.8% in the Cinacalcet -treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Cinacalcet -treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown.

Patients with Parathyroid Carcinoma or Primary Hyperparathyroidism

Serum calcium should be measured within 1 week after initiation or dose adjustment of Cinacalcet . Once maintenance dose levels have been established, serum calcium should be measured every 2 months.

There is no sufficient scientific evidence traceable regarding use and safety of Cinacalcet in concurrent use with alcohol.

It is not known if cinacalcet is present in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Pregnancy Category C

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on Area Under the Curve [AUC] comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).

In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day. Cinacalcet has been shown to cross the placental barrier in rabbits.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain.

There are no adequate and well-controlled studies of Cinacalcet in pregnant women. Cinacalcet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The adverse reactions related to Cinacalcet can be categorized as

Common Adverse effects:

Dizziness, muscle pain (myalgia) , weakness (asthenia) ,rash , reduced testosterone levels ,high potassium levels in the blood (hyperkalemia), allergic reactions (hypersensitivity), headache.

Less Common Adverse effects:

Seizures (convulsions or fits) ,low blood pressure (hypotension) , upper respiratory infection , breathing difficulties (dyspnoea) , cough , indigestion (dyspepsia) ,diarrhea, abdominal pain, constipation , muscle spasms , back pain , low calcium levels in the blood.

Rare Adverse effects:

Hives, Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (angioedema).

The clinically relevant drug interactions of Cinacalcet is briefly summarized here

• Increased risk of hypocalcemia with other agents known to reduce the serum Ca levels.
• Increased plasma concentration with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, telithromycin, ritonavir).
• Significantly increased exposure of drugs primarily metabolized by CYP2D6 (e.g. desipramine, nortriptyline, metoprolol, flecainide, propafenone, dextromethorphan).

The most common side effects of Cinacalcet includes: Dizziness, muscle pain (myalgia) , weakness (asthenia) ,rash , reduced testosterone levels ,high potassium levels in the blood (hyperkalemia), allergic reactions (hypersensitivity), headache.

Pregnancy Category (FDA):

Pregnancy Category C

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on Area Under the Curve [AUC] comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).

In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day. Cinacalcet has been shown to cross the placental barrier in rabbits.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain.

There are no adequate and well-controlled studies of Cinacalcet in pregnant women. Cinacalcet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

There is no FDA guidance on use of Cinacalcet during labor and delivery.

Nursing Mothers

Studies in rats have shown that Cinacalcet is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats, and because many drugs are excreted in human milk and there is a potential for clinically significant adverse reactions in infants who ingest Cinacalcet , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.

Pediatric Use

There is no FDA guidance on the use of Cinacalcet with respect to pediatric patients.

Geriatric Use

Of the 1136 patients enrolled in the Cinacalcet phase 3 clinical program in patients with CKD on dialysis, 26% were ≥ 65 years old, and 9% were ≥ 75 years old. No differences in the safety and efficacy of Cinacalcet were observed in patients greater or less than 65 years of age. No dosage adjustment is required for geriatric patients.

Gender

There is no FDA guidance on the use of Cinacalcet with respect to specific gender populations.

Race

There is no FDA guidance on the use of Cinacalcet with respect to specific racial populations.

Renal Impairment

No dosage adjustment is necessary for renal impairment.

Hepatic Impairment

Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Cinacalcet because cinacalcet exposure is increased by 2.4 and 4.2 fold, respectively, in these patients.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Cinacalcet in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Cinacalcet in patients who are immunocompromised.

Symptoms: Hypocalcemia manifested by myalgia, paranesthesia, cramping, tetany, and seizures.

Management: Symptomatic and supportive treatment.

Pharmacodynamics:

Cinacalcet is a phenylethylamine calcimimetic agent that binds to and increases the sensitivity of Ca-sensing receptors of the parathyroid glands to extracellular Ca. This activity lowers the PTH concentrations and leads to a concomitant decrease in serum Ca and phosphorus levels, thereby preventing progressive bone disease and complications associated with mineral metabolism disorders.

Pharmacokinetics:

Absorption: Increased bioavailability and peak plasma concentrations with food. Absolute bioavailability: Approx 20-25% (fasted state). Time to peak plasma concentration: Approx 2-6 hours.

Distribution: Extensively distributed in the body. Volume of distribution: Approx 1,000 L. Plasma protein binding: Approx 93-97%.

Metabolism: Rapidly and extensively metabolised in the liver primarily by CYP3A4, CYP1A2, and CYP2D6 isoenzymes via oxidative N-dealkylation and oxidation of the naphthalene ring into inactive metabolites.

Excretion: Mainly via urine (approx 80% as metabolites); faeces (approx 15%). Elimination half-life: Approx 6 hours (initial); 30-40 hours (terminal).

1. https://www.uptodate.com/contents/ Cinacalcet -drug-information?search= Cinacalcet &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Cinacalcet _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Cinacalcet ?type=full&mtype=generic#mechanism-of-action