Cinacalcet

Sensipar comes in the form of a tablet to take by mouth. It's typically taken once or twice a day, with food or shortly after a meal.

The starting dose is usually 30 milligrams (mg). Your doctor will probably start you on a low dose of Sensipar and gradually increase it.

Try to take this medicine around the same time each day.

Don't split, chew, or crush the tablets. Swallow them whole.

Follow the instructions on your prescription label carefully when taking this drug. Don't take more or less Sensipar than is recommended.

Sensipar Overdose

Symptoms of a Sensipar overdose (which are similar to the symptoms of low calcium levels, or hypocalcemia) include:

• Muscle aches or cramps
• Sudden tightening of the muscles in the hands, feet, face, or throat
• Burning or tingling of the lips, tongue, fingers, or feet
• Seizures

If you suspect an overdose, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Sensipar

If you miss a dose of Sensipar, take it as soon as you remember.

But skip the missed dose if it's almost time for your next scheduled dose.

Don't double up on doses to make up for a missed one.

Sensipar (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Sensipar tablets contain the hydrochloride salt of cinacalcet. Its empirical formula is C22H22F3N·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. The 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.

Sensipar 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 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:

Inactive Ingredients

The following are the inactive ingredients in Sensipar tablets: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide and magnesium stearate. Tablets are coated with color (Opadry®II green), clear film coat (Opadry®clear), and carnauba wax.

Dosage Forms And Strengths

Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “30” or “60” or “90” on the opposite side of the 30 mg, 60 mg, or 90 mg strengths, respectively.

Storage And Handling

Sensipar 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “30” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-073-30)

Sensipar 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “60” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-074-30)

Sensipar 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “90” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-075-30)

Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). [See USP controlled room temperature].

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799. Revised: March 2017

Mechanism Of Action

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 Sensipar, 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.

Pharmacodynamics

Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (Cmax) 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.

Pharmacokinetics

After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Cinacalcet Cmax 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 Cmax 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 a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of 30 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.

Specific Populations

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) [see Use In Specific Populations].

The pharmacokinetics of cinacalcet has not been studied in patients < 18 years of age [see Use In Specific Populations].

The disposition of a 50 mg Sensipar 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 [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

The pharmacokinetic profile of a 75 mg Sensipar 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 [see Use In Specific Populations].

Drug Interactions

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

Table 5. Effect of co-administered drugs on cinacalcet

Table 6. Effect of cinacalcet co-administration on other drugs

Clinical Studies

Secondary Hyperparathyroidism In Patients With Chronic Kidney Disease On Dialysis

Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to Sensipar and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P product was 61 mg2/dL2 . The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% on peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of ≤ 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH ≤ 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of patients in the Sensipar arm and 80% of the patients in the placebo arm completed the 6-month studies. In the primary efficacy analysis, 40% of the patients on Sensipar and 5% of placebo-treated patients achieved an iPTH ≤ 250 pg/mL (p < 0.001) (Table 7, Figure 1). These studies showed that Sensipar reduced iPTH while lowering Ca x P, calcium, and phosphorus levels (Table 7, Figure 2). The median dose of Sensipar at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.

Similar results were observed when either the iPTH or biointact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.

Table 7. Effects of Sensipar on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis)

Figure 1. Mean (SE) iPTH Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies)

Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.

Sensipar decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH ≥ 300 to ≤ 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of ≤ 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.

Parathyroid Carcinoma

Twenty-nine patients with Parathyroid Carcinoma were enrolled in a single-arm, open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg four times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was ≤ 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Twenty-nine patients entered the study. The median exposure to cinacalcet was 229 days (range: 1 to 1051). At baseline the mean (SE) serum calcium was 14.1 (0.4) mg/dL. At the end of the titration phase, the mean (SE) serum calcium was 12.4 (0.5) mg/dL, which is a mean reduction of 1.7 (0.6) mg/dL from baseline. Figure 3 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice daily to 90 mg four times daily.

Figure 3. Serum Calcium Values in Patients With Parathyroid Carcinoma Receiving Sensipar at Baseline, Titration, and Maintenance Phase

Patients With Hypercalcemia Due To Primary Hyperparathyroidism

Seventeen patients with severe hypercalcemia due to primary HPT, who had failed or had contraindications to parathyroidectomy, participated in an open-label, single-arm study. The study consisted of two phases, a dose-titration phase and a maintenance phase. In this trial, severe hypercalcemia was defined as a screening serum calcium level of > 12.5 mg/dL. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg 4 times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was ≤ 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.

Seventeen patients entered the study. The median exposure to cinacalcet was 270 days (range: 32 to 1,105). At baseline the mean (SE) serum calcium was 12.7 (0.2) mg/dL. At the end of the titration phase the mean (SE) serum calcium was 10.4 (0.3) mg/dL, which is a mean reduction of 2.3 (0.3) mg/dL from baseline. Figure 4 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice a day to 90 mg four times a day.

Figure 4. Mean Serum Calcium (SE) at Baseline, End of Titration, and Scheduled Maintenance Visits (Patients with Severe intractable primary HPT)

Sixty-seven patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dL [2.82 mmol/L] and ≤ 12.5 mg/dL [3.12 mmol/L]), but who were unable to undergo parathyroidectomy participated in a randomized, double-blind, placebo-controlled study. A total of 33 patients were randomized to Sensipar and 34 patients randomized to placebo. The mean age of the patients was 72 years, 52% were female, 61% were Caucasian, and 5% were Blacks. The study started with a 12-week titration phase, followed by a 16-week efficacy assessment phase. Cinacalcet was initiated at a dose of 30 mg twice daily and titrated to maintain a corrected total serum calcium concentration within the normal range. During the efficacy period a significantly higher percentage of cinacalcet-treated patients compared with the placebo-treated patients achieved mean corrected total serum calcium concentration (≤ 10.3 mg/dL [2.57 mmol/L], 75.8% vs 0%, p < 0.001) and ≥ 1 mg/dL [0.25 mmol/L] decrease from baseline in mean corrected total serum calcium concentration (84.8% vs 5.9%, p < 0.001). The median dose of Sensipar at the completion of the study was 60 mg/day.

Oral Administration

Take with food or shortly after meal

Swallow tablet whole, do not chew, crush, or divide

Serious side effects have been reported with cinacalcet, including the following:

• Cinacalcet can lower calcium levels in the blood and can cause tingling, muscle pain, muscle cramping, and convulsions.
• Cinacalcet may lower the seizure threshold in patients with a history of seizure disorders.

Do not take cinacalcet if:                        

• your blood levels of calcium are low.
• you are allergic to cinacalcet or any of its ingredients.

Cinacalcet decreases levels of parathyroid hormone (PTH), calcium, and phosphorous in the body.

Cinacalcet is used to treat hyperparathyroidism (overactive functioning of the parathyroid glands) in people who are on long-term dialysis for kidney disease.

Cinacalcet is also used to lower calcium levels in people with cancer of the parathyroid gland.

Cinacalcet may also be used for purposes not listed in this medication guide.

You should not take this medication if you are allergic to cinacalcet.

Before you take cinacalcet, tell your doctor if you have high blood pressure, heart disease, heart failure, a heart rhythm disorder, liver disease, or a history of seizures.

There are many other medicines that can interact with cinacalcet. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Cinacalcet works best if you take it with food or shortly after eating a meal.

Do not crush or break a cinacalcet tablet. Swallow the pill whole.

To be sure this medication is helping your condition, your blood may need to be tested often. Visit your doctor regularly.

Call your doctor at once if you have a serious side effect such as numbness or tingly feeling around your mouth, fast or slow heart rate, muscle tightness or contraction, overactive reflexes, seizure, feeling short of breath, swelling, rapid weight gain, or feeling like you might pass out.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

You should not use cinacalcet if you are allergic to it, or if you have:

• low levels of calcium in your blood (hypocalcemia).

To make sure cinacalcet is safe for you, tell your doctor if you have ever had:

• high or low blood pressure;

• heart disease, heart failure, heart rhythm disorder;

• personal or family history of long QT syndrome;

• a stomach ulcer or severe vomiting;

• liver disease;

• seizures; or

• if you have kidney disease and you are not on dialysis.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether cinacalcet passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking this medicine.

Cinacalcet is not approved for use by anyone younger than 18 years old.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

It is very important that your doctor check your progress at regular visits to make sure that cinacalcet is working properly. Blood tests may be needed to check for unwanted effects.

cinacalcet may lower the calcium in your blood. If you have any of these symptoms, check with your doctor right away: abdominal or stomach cramps, confusion, convulsions, difficulty with breathing, irregular heartbeats, mood or mental changes, muscle cramps in the hands, arms, feet, legs, or face, numbness and tingling around the mouth, fingertips, or feet, shortness of breath, or tremors.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

Do not take other medicines unless they have been discussed with your doctor. Taking other medicines together with cinacalcet may require your doctor to change the dose of one of the medicines or cinacalcet.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

(sin a KAL cet)

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

Hyperparathyroidism, secondary: Oral: Initial: 30 mg once daily; increase dose incrementally every 2 to 4 weeks (to 60 mg once daily, 90 mg once daily, 120 mg once daily, and 180 mg once daily) as necessary to maintain intact parathyroid hormone (iPTH) level between 150 to 300 pg/mL. May be used alone or in combination with vitamin D and/or phosphate binders.

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

Concerns related to adverse effects:

• Adynamic bone disease: May develop if intact parathyroid hormone (iPTH) levels are suppressed <100 pg/mL; reduce dose or discontinue use of cinacalcet and/or vitamin D if iPTH levels decrease below 150 pg/mL.

• Cardiovascular effects: QT prolongation and ventricular arrhythmia secondary to hypocalcemia may occur. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk. Closely monitor corrected serum calcium and QT interval. Cases of idiosyncratic hypotension, worsening of heart failure, and/or arrhythmia have been reported in patients with impaired cardiovascular function; may correlate with decreased serum calcium.

• GI effects: GI bleeding, mostly upper GI bleeding, have been reported (exact cause unknown); patients with risk factors for upper GI bleeding (eg, gastritis, esophagitis, ulcers, severe vomiting) may be at increased risk. Monitor for worsening of common GI adverse reactions of nausea and vomiting and for signs and symptoms of GI bleeding and ulcerations during therapy.

• Hypocalcemia: Life-threatening and fatal events associated with hypocalcemia have occurred. Monitor serum calcium and for symptoms of hypocalcemia (eg, muscle spasms, myalgia, paresthesia, seizure, tetany). Use with caution in patients receiving concomitant therapies known to lower serum calcium concentrations. May require treatment interruption, dose reduction, or initiation (or dose increases) of calcium-based phosphate binder and/or vitamin D to raise serum calcium depending on calcium levels or symptoms of hypocalcemia. Do not initiate therapy if the corrected serum calcium is less than the lower limit of normal; corrected serum calcium must be at or above the lower limit of normal prior to initiation, dose increase, or reinitiation.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with moderate-to-severe hepatic impairment (Child-Pugh classes B and C); cinacalcet exposure and half-life are increased; monitor serum calcium, serum phosphorus and iPTH closely.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; seizure threshold is lowered by significant serum calcium reductions. Monitor calcium levels closely.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Not indicated for chronic kidney disease (CKD) patients not receiving dialysis. In the US, the long-term safety and efficacy of cinacalcet has not been evaluated in CKD patients with hyperparathyroidism not requiring dialysis. Although possibly related to lower baseline calcium levels, clinical studies have shown an increased incidence of hypocalcemia (<8.4 mg/dL) in patients not requiring dialysis.

Commonly reported side effects of cinacalcet include: decreased plasma testosterone, diarrhea, dizziness, myalgia, nausea, vomiting, and hypoparathyroidism. Other side effects include: dialysis access infection, asthenia, chest pain, hypertension, hypotension, and anorexia. See below for a comprehensive list of adverse effects.

Applies to cinacalcet: oral tablet

Cardiovascular

Very common (10% or more): Hypotension (11.6%)
Common (1% to 10%): Hypertension
Frequency not reported: Worsening heart failure, QT prolongation and ventricular arrhythmia secondary to hypocalcemia[Ref]

Gastrointestinal

Very common (10% or more): Nausea (31%), vomiting (27%), diarrhea (21%), dyspepsia (13%), abdominal pain (10.9%)
Common (1% to 10%): Upper abdominal pain, dyspepsia, anorexia, constipation[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity reactions
Postmarketing reports: Rash, angioedema, urticaria[Ref]

Local

Common (1% to 10%): Access site infection[Ref]

Dermatologic

Very common (10% or more): Paresthesia (14 to 29%)
Very rare (less than 0.01%): Leukocytoclastic vasculitis with palpable purpura on both upper and lower extremities[Ref]

Hematologic

Common (1% to 10%): Anemia[Ref]

Metabolic

Very common (10% or more): Hypocalcemia (11.2%)
Common (1% to 10%): Hyperkalemia, dehydration[Ref]

Respiratory

Very common (10% or more): Cough (11.7%), upper respiratory infection (11%)
Common (1% to 10%): Dyspnea[Ref]

Endocrine

Common (1% to 10%): Reduced testosterone levels[Ref]

Musculoskeletal

Very common (10% or more): Myalgia (15%), muscle spasms (11%)
Common (1% to 10%): Limb pain, back pain, fracture, arthralgia, noncardiac chest pain[Ref]

Nervous system

Very common (10% or more): Paresthesia (up to 29%), headache (11.5%), dizziness (10%)
Common (1% to 10%): Fatigue, seizures[Ref]

Other

Common (1% to 10%): Asthenia[Ref]

Renal

Common (1% to 10%): Dialysis access site infection[Ref]

Some side effects of cinacalcet may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Initial dose: 30 mg orally twice a day
Titration: Titrate dose every 2 to 4 weeks through sequential doses of 30 mg orally twice a day, 60 mg orally twice a day, 90 mg orally twice daily, and 90 mg 3 or 4 times a day
Maintenance dose: 60 to 360 mg orally per day
Maximum dose: 90 mg orally 4 times a day

Comments:
-Tablets should be taken whole and not divided.
-This drug should be taken with food or shortly after a meal.
-Serum calcium should be measured within 1 week after initiation or dose adjustment. Once maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months. After titration to the maximum dose, serum calcium should be periodically monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of therapy should be considered.

Use: Parathyroid carcinoma and primary hyperparathyroidism who are unable to undergo parathyroidectomy

This drug is excreted into the milk of lactating rats with a high milk-to-plasma ratio and is associated with decreased food consumption and reduced body weight gain of suckling rats.

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comment: The effects in the nursing infant are unknown.

The following adverse reactions are discussed in greater detail in other sections of labeling:

•   Hypocalcemia [see Warnings and Precautions (5.1)]
•   Upper Gastrointestinal Bleeding [see Warnings and Precautions (5.2)]
•   Hypotension, Worsening Heart Failure and/or Arrhythmias [see Warnings and Precautions (5.3)]
•   Adynamic Bone Disease [see Warnings and Precautions (5.4)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Cinacalcet, 470 placebo) for up to 6 months. The most frequently reported adverse reactions are listed in Table 1.

Seizures were observed in 1.4% (13/910) of Cinacalcet-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo controlled trials.

In a randomized, double-blind placebo controlled study of 3-883 patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the Cinacalcet group), the most frequently reported adverse reactions (incidence of ≥ 5% in the Cinacalcet group and a difference ≥ 1% compared to placebo) are listed in Table 2.

Additional adverse reaction rates from the long-term, randomized, double-blind placebo controlled study for Cinacalcet tablets versus placebo are as follows: seizure (2.5%, 1.6%), rash (2.2%, 1.9%), hypersensitivity reactions (9.4%, 8.3%).

Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism

The safety profile of Cinacalcet hydrochloride tablets in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with Cinacalcet hydrochloride tablets in a single arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms.

Eight patients died during treatment with Cinacalcet hydrochloride tablets in this study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT. Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage (1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in three patients (7%).

Seizures were observed in 0.7% (1/140) of Cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies.

Hypocalcemia

In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving Cinacalcet hydrochloride tablets compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29% of patients receiving Cinacalcet hydrochloride tablets compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.

In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the Cinacalcet group), 75% of patients receiving Cinacalcet hydrochloride tablets compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of Cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL. Most of the cases of severe hypocalcemia less than 7.5 mg/dL (21/33=64%) occurred during the first 6 months. In this trial, 1.1% of patients receiving Cinacalcet hydrochloride tablets and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia.

Hypocalcemia

In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving Cinacalcet hydrochloride tablets compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29 % of patients receiving Cinacalcet hydrochloride tablets compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.

In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the Cinacalcet group), 75% of patients receiving Cinacalcet hydrochloride tablets compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of Cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL. Most of the cases of severe hypocalcemia less than 7.5mg/dL (21/33=64%) occurred during the first 6 months. In this trial, 1.1% of patients receiving Cinacalcet hydrochloride tablets and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Cinacalcet tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Rash and hypersensitivity reactions (including angioedema, and urticaria), and myalgia have been identified as adverse reactions during post approval use of Cinacalcet tablets. Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in Cinacalcet-treated patients with impaired cardiac function in postmarketing safety surveillance [see Warnings and Precautions (5.1)].

• Rash and hypersensitivity reactions (including angioedema and urticaria), and myalgia
• Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function
• Gastrointestinal bleeding

Mechanism of Action

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 hydrochloride tablets, 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.

Pharmacodynamics

Reduction in iPTH levels correlated with the plasma Cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (Cmax) 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.

Pharmacokinetics

After oral administration of Cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Cinacalcet Cmax 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 Cmax 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 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and Cmax of Cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of Cinacalcet does not change over time with once daily dosing of 30 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.

Metabolism and Excretion

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.

Specific Populations

Age: 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) [see Use in Specific Populations (8.5)].

Hepatic Impairment

The disposition of a 50 mg Cinacalcet hydrochloride 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 [see Use in Specific Populations (8.7)].

Renal Impairment

The pharmacokinetic profile of a 75 mg Cinacalcet hydrochloride 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 [see Use in Specific Populations (8.6)].

Drug Interactions

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