ENDOLET

Cinacalcet tablets contain the hydrochloride salt of cinacalcet, a positive modulator of the calcium sensing receptor.

The empirical formula for cinacalcet is

C 22 H 22 F 3 N⋅HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base).

It has one chiral center having an R-absolute configuration.

R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.

The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.

The hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula: Cinacalcet tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).

The following are the inactive ingredients in cinacalcet tablets: pre-gelatinized starch (botanical source is maize starch), microcrystalline cellulose, povidone, crospovidone, magnesium stearate and isopropyl alcohol.

Tablets are coated with Opadry II

Green (hypromellose, lactose monohydrate, titanium dioxide, triacetin, FD&C blue #2/indigo carmine AL, iron oxide yellow).

Cinacalcet is a positive modulator of the calcium sensing receptor indicated for: Secondary Hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis.

Cinacalcet tablets are not indicated for use in patients with CKD who are not on dialysis Hypercalcemia in adult patients with Parathyroid Carcinoma (PC).

Hypercalcemia in adult patients with primary

HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. 1.1 Secondary Hyperparathyroidism Cinacalcet tablets are indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis.

Cinacalcet tablets are not indicated for use in patients with CKD who are not on dialysis because of an increased risk of hypocalcemia. 1.2 Parathyroid Carcinoma Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma. 1.3 Primary Hyperparathyroidism Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. .

QT space extension, history (of) History of seizures Child less than 12.5 kg Child under 6 years of age Child between and 18 years Pregnancy Heart failure Moderate to severe hepatic impairment Chronic end-stage renal impairment Subject at risk of QT space prolongation Subject at risk of digestive haemorrhage Smoking Treatment with a hypocalceminant medicine.

The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion.

Cinacalcet, the active ingredient in cinacalcet tablets is a calcimimetic agent that directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to activation by extracellular calcium.

The reduction in

PTH is associated with a concomitant decrease in serum calcium levels. 12.2 Pharmacodynamics Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD.

The nadir in iPTH level occurs approximately to 6 hours post dose, corresponding with the maximum plasma concentration (C max ) of cinacalcet.

After steady-state cinacalcet concentrations are reached (which occurs within 7 days of dose change), serum calcium concentrations remain constant over the dosing interval in patients with CKD.

Reductions in

PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT. 12.3 Pharmacokinetics Absorption and Distribution After oral administration of cinacalcet, C max is achieved in approximately to 6 hours.

Cinacalcet C max and

AUC (0-infinite) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers.

The C max and

AUC (0-infinite) of cinacalcet were increased by 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.

After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and terminal half-life of to 40 hours.

Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately with once daily oral administration.

The median accumulation ratio is approximately to 5 with twice daily oral administration.

The AUC and

C max of cinacalcet increase proportionally over the dose range of to 180 mg once daily.

The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of to 180 mg. The volume of distribution is approximately 1000 L, indicating extensive distribution.

Cinacalcet is approximately 93% to 97% bound to plasma protein(s).

The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.

Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2.

After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via β-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug forming dihydrodiols, which are further conjugated with glucuronic acid.

The plasma concentrations of the major circulating metabolites, including the cinnamic acid derivatives and glucuronidated dihydrodiols, markedly exceed the parent drug concentrations.

The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity.

Renal excretion of metabolites was the primary route of elimination of radioactivity.

Approximately 80% of the dose was recovered in the urine and 15% in the feces.

Geriatric Population The pharmacokinetic profile of cinacalcet in geriatric patients (age ≥ 65 years, n = 12) is similar to that for patients who are < 65 years of age (n = 268) .

The disposition of a 50 mg cinacalcet tablets single dose was compared between patients with hepatic impairment and patients with normal hepatic function.

Cinacalcet exposure (AUC (0-infinite) ) was comparable between healthy volunteers and patients with mild hepatic impairment.

However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures (AUC (0-infinite) ) were 2.4 and 4.2 fold higher, respectively, than that in healthy volunteers.

The mean half-life of cinacalcet increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively.

Protein binding of cinacalcet is not affected by impaired hepatic function.

The pharmacokinetic profile of a 75 mg cinacalcet tablets single dose in patients with mild, moderate, and severe renal impairment, and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers.

In vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4.

In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes.

Tables and 6 list the findings from in vivo drug-drug interaction studies.

Table 5.

Effect of co-administered drugs on cinacalcet

Co-administered drug and dosing regimen Cinacalcet Dose Single dose.

Mean change in

AUC (0-inf) Mean change in C max 200 mg ketoconazole twice daily for 7 days 90 mg on day 5 ↑127% ↑116% 1500 mg calcium carbonate, single dose 100 mg ↓6% ↓5% 80 mg pantoprazole daily for 3 days 90 mg on day 3 ↑1% ↓3% 2400 mg sevelamer HCl three times a day for 2 days 90 mg on day with first dose of sevelamer ↓4% ↓7% Table 6.

Effect of cinacalcet co-administration on other drugs Cinacalcet dosing regimen Co-administered drug Name and Dose Mean change in AUC (0-inf) Mean change in C max 30 mg twice daily for 8 days 25 mg warfarin No significant change in prothrombin time. tablet Single dose on day 5. ↑1 % for R-warfarin ↓1% for S-warfarin ↓10 % for R-warfarin ↓12 % for S-warfarin 90 mg daily for 7 days to CYP2D6 extensive metabolizers 50 mg desipramine ↑264% ↑75% 90 mg daily for 5 days 2 mg midazolam † ↑5% ↓5% 25 or 100 mg single dose to CYP2D6 extensive metabolizers 50 mg amitriptyline single dose ↑21-22% for amitriptyline ↑17-23% for nortriptyline Nortriptyline is an active metabolite of amitriptyline. ↑13-21% for amitriptyline ↑11-15% for nortriptyline.

Mechanism of action

The calcium-sensitive receptor present on the surface of the main cell of the parathyroid gland is the main regulator of PTH secretion.

Cinacalcet is a calcimetic agent that directly lowers the PTH level by increasing the sensitivity of the receptor to extracellular calcium.

The decrease in

PTH is associated with a concomitant reduction in serum calcium.

The reduction in

PTH is correlated with the concentration of cinacalcet.

At steady state, serum calcium remains stable between two doses.

• Hyperkalaemia (Common)
• Testosteroneaemia (decrease) (Common)
• Hypocalcaemia (Common)
• Rash (Common)
• Urticaria Asthenia (Common)
• Hypersensitivity (Common)
• Angioedema Appetite decreased (Common)
• Anorexia (Common)
• Feeling dizzy (Common)
• Hypotension (Common)
• Heart failure (aggravation)
• Ventricular arrhythmia QT space extension Nausea (Very common)
• Abdominal pain (Common)
• Diarrhoea (Common)
• Constipation (Common)
• Epigastric pain (Common)
• Vomiting (Very common)
• Dyspepsia (Common)
• Muscle spasm (Common)
• Muscle pain (Common)
• Sleeping (Common)
• Headache (Common)
• Epilepsy (Common)
• Convulsions (Common)
• Paraesthesia (Common)
• Dyspnoea (Common)
• Cough (Common)
• Upper respiratory tract infection (Common).

Overdosage of cinacalcet may lead to hypocalcemia.

In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels.

Since cinacalcet is highly protein bound, hemodialysis is not an effective treatment for overdosage of cinacalcet tablets.

Cinacalcet tablets treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range.

Cinacalcet tablets should be taken with food or shortly after a meal.

Tablets should always be taken whole and not divided Secondary HPT in patients with CKD on dialysis: Starting dose is 30 mg once daily.

Titrate dose no more frequently than every to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily as necessary to achieve targeted intact parathyroid hormone (iPTH) levels. iPTH levels should be measured no earlier than 12 hours after most recent dose.

Hypercalcemia in patients with

PC or hypercalcemia in patients with primary HPT: Starting dose is 30 mg twice daily.

Titrate dose every to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalize serum calcium levels.

Once the maintenance dose has been established, monitor serum calcium approximately monthly for patients with secondary HPT and every 2 months for patients with PC or primary HPT 2.1 Administration Cinacalcet tablets should be taken with food or shortly after a meal.

Cinacalcet tablets are administered orally and should always be taken whole and not chewed, crushed, or divided. 2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis The recommended starting oral dose of cinacalcet tablets is 30 mg once daily.

Serum calcium and serum phosphorus should be measured within 1 week and intact parathyroid hormone (iPTH) should be measured to 4 weeks after initiation or dose adjustment of cinacalcet tablets.

Cinacalcet tablets should be titrated no more frequently than every to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily to target iPTH levels of to 300 pg/mL.

Serum iPTH levels should be assessed no earlier than 12 hours after dosing with cinacalcet tablets.

Cinacalcet tablets can be used alone or in combination with vitamin D sterols and/or phosphate binders.

During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with cinacalcet tablets. 2.3 Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism The recommended starting oral dose of cinacalcet tablet is 30 mg twice daily.

The dose of cinacalcet tablets should be titrated every to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels.

Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet tablets. 2.4 Switching from Parsabiv (etelcalcetide) to Cinacalcet Discontinue etelcalcetide for at least 4 weeks prior to starting Cinacalcet.

Ensure corrected serum calcium is at or above the lower limit of normal prior to Cinacalcet initiation.

Cinacalcet treatment at a starting dose of 30 mg once daily. 2.5 Monitoring for Hypocalcemia Once the maintenance dose has been established, serum calcium should be measured approximately monthly for patients with secondary hyperparathyroidism with CKD on dialysis, and every 2 months for patients with parathyroid carcinoma or primary hyperparathyroidism.

For secondary hyperparathyroidism patients with

CKD on dialysis, 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 tablets 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 tablets.

Cinacalcet 30 mg tablets are formulated as light-green, film-coated, oval-shaped, biconvex tablets debossed with "CL" on one side and "410" on the opposite side, packaged in bottles of 30 tablets. (NDC 69097-410-02).

Cinacalcet 60 mg tablets are formulated as light-green, film-coated, oval-shaped, biconvex tablets debossed with "CL" on one side and "411" on the opposite side, packaged in bottles of 30 tablets. (NDC 69097-411-02).

Cinacalcet 90 mg tablets are formulated as light-green, film-coated, oval-shaped, biconvex tablets debossed with "CL" on one side and "412" on the opposite side, packaged in bottles of 30 tablets. (NDC 69097-412-02).

Store at 25 °C (77 °F), excursions permitted from 15 °C to 30 °C (59°F to 86°F). .

The safety and efficacy of cinacalcet tablets have not been established in pediatric patients.

The use of Cinacalcet for the treatment of secondary HPT in pediatric patients with CKD on dialysis was evaluated in two randomized, controlled studies (Pediatric Study and Study 2) where 47 pediatric patients aged 6 years to less than 18 years received at least one dose of Cinacalcet and in one single-arm study (Pediatric Study 3) where 17 pediatric patients aged 28 days to less than 6 years received at least one dose of Cinacalcet.

Dosing with cinacalcet in a Pediatric

Study was stopped because of a fatality in a cinacalcet-treated individual.

The individual was noted to be severely hypocalcemic at the time of death.

The cause of death was multifactorial and a contribution of cinacalcet to the death could not be excluded.

Study was terminated and changes to

Cinacalcet dosing after the fatality were implemented in Pediatric Study and Study to minimize the risk of severe hypocalcemia.

The data in Pediatric

Studies and 3 were insufficient to establish the safety and efficacy of Cinacalcet for the treatment of secondary HPT in pediatric patients with CKD on dialysis.

In aggregate, the pediatric studies did not establish a safe and effective Cinacalcet dosing regimen for the pediatric population.

Of the total number of subjects (n=1136) in clinical studies of cinacalcet tablets, 26 percent were and over, and 9 percent were and over.

No overall differences in the safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.