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CINACALCET

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cinacalcet is a second generation orally active calcimimetic drug that binds to the calcium-sensing receptors of the parathyroid glands and increases the sensitivity for receptor activation by extracellular calcium, which reduces parathyroid hormone release.

Specific Substances

    1) Cinacalcet hydrochloride
    2) AMG 073
    3) CAS 364782-34-3
    1.2.1) MOLECULAR FORMULA
    1) C22H22F3N-HCl

Available Forms Sources

    A) FORMS
    1) Cinacalcet is available as 30 mg, 60 mg, and 90 mg tablets (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) USES
    1) Cinacalcet is indicated for the treatment of hypercalcemia in patients with primary hyperparathyroidism, secondary hyperparathyroidism in patients with chronic kidney disease receiving hemodialysis, and for the treatment of hypercalcemia in patients with parathyroid carcinoma (Prod Info SENSIPAR(R) oral tablets, 2014; Iqbal et al, 2003).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cinacalcet is indicated for the treatment of hypercalcemia in patients with primary hyperparathyroidism, secondary hyperparathyroidism in patients with chronic kidney disease receiving hemodialysis, and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
    B) PHARMACOLOGY: Cinacalcet, a calcimimetic agent, enhances the sensitivity of the calcium sensing receptor to extracellular calcium, thus, directly reducing the levels of parathyroid hormone (PTH) and serum calcium levels.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects during clinical trials, with an incidence greater than 25%, were nausea and vomiting.
    2) INFREQUENT: Other adverse effects reported less frequently include hypocalcemia, hyperkalemia, headache, paraesthesias, fatigue, hypertension, diarrhea, anxiety, anorexia, dyspepsia, abdominal pain, constipation, hypersensitivity reactions, myalgia, muscle spasms, dizziness, hypotension, asthenia, dyspnea, cough, and non-cardiac chest pain.
    3) RARE: Seizures, QT prolongation secondary to hypocalcemia, and rash have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Doses up to 300 mg daily in dialysis patients have been well-tolerated. Overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.
    0.2.20) REPRODUCTIVE
    A) Cinacalcet is classified as FDA pregnancy category C. Animal studies have shown maternal toxicities and fetal toxicities with exposure at higher than expected human dose. Cinacalcet is excreted in breast milk in animal studies with a high milk-to-plasma ratio.

Laboratory Monitoring

    A) Monitor serial serum calcium concentrations. Nadir in serum calcium can occur 8 to 12 hours after a single therapeutic dose.
    B) Institute continuous cardiac monitoring and obtain a baseline ECG to evaluate for evidence of QTc prolongation or dysrhythmias in patients with a significant exposure. Although rare with cinacalcet therapy, QTc prolongation and ventricular dysrhythmias can occur secondary to hypocalcemia.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor vital signs and mental status.
    E) Plasma cinacalcet concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Intravenous administration of calcium gluconate or calcium chloride may be required for significant hypocalcemia. Institute continuous cardiac monitoring and monitor ECG for evidence of QT prolongation or dysrhythmias. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL/HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) There is no available antidote.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent ingestion of 1 or 2 tablets, who remains asymptomatic, can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance, including serial serum calcium concentrations, until they are clearly improving and clinically stable. Nadir in serum calcium occurs 8 to 12 hours after a single therapeutic dose.
    3) HOSPITAL CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Patients with evidence of severe hypocalcemia (eg, paresthesias, myalgias, tetany, QT interval prolongation, dysrhythmias, seizures) should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected cinacalcet overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    I) PHARMACOKINETICS
    1) Approximately 93% to 97% plasma protein bound. Volume of distribution is 1000 liters. Cinacalcet is primarily metabolized via various cytochrome P450 enzymes (ie, CYP3A4, CYP2D6, and CYP1A2) Plasma concentrations of the major circulating metabolites, which include the cinnamic acid derivatives and glucuronidated dihydrodiols, can markedly exceed parent drug concentrations. Following administration of a 75-mg radiolabeled dose to healthy volunteers, renal excretion of metabolites was the primary route of elimination of radioactivity, and approximately 80% of the dose was recovered in the urine. In healthy volunteers, once cinacalcet is absorbed concentrations decline in a biphasic fashion with a terminal half-life of 30 to 40 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents or conditions that may cause hypocalcemia (eg, bisphosphonates, hypoparathyroidism, vitamin D deficiency)

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Doses up to 300 mg/day (titrated) have been tolerated in hemodialysis patients.
    B) THERAPEUTIC DOSE: ADULTS: For secondary hyperparathyroidism, the recommended starting dose is 30 mg daily titrated up to 180 mg once daily as necessary. For the treatment of parathyroid carcinoma or primary hyperparathyroidism, the recommended dose is 30 mg twice daily , titrated up to 90 mg 3 to 4 times daily (270 mg to 360 mg daily) as necessary. PEDIATRIC: Safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Cinacalcet is indicated for the treatment of hypercalcemia in patients with primary hyperparathyroidism, secondary hyperparathyroidism in patients with chronic kidney disease receiving hemodialysis, and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
    B) PHARMACOLOGY: Cinacalcet, a calcimimetic agent, enhances the sensitivity of the calcium sensing receptor to extracellular calcium, thus, directly reducing the levels of parathyroid hormone (PTH) and serum calcium levels.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects during clinical trials, with an incidence greater than 25%, were nausea and vomiting.
    2) INFREQUENT: Other adverse effects reported less frequently include hypocalcemia, hyperkalemia, headache, paraesthesias, fatigue, hypertension, diarrhea, anxiety, anorexia, dyspepsia, abdominal pain, constipation, hypersensitivity reactions, myalgia, muscle spasms, dizziness, hypotension, asthenia, dyspnea, cough, and non-cardiac chest pain.
    3) RARE: Seizures, QT prolongation secondary to hypocalcemia, and rash have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Doses up to 300 mg daily in dialysis patients have been well-tolerated. Overdose effects are anticipated to be an extension of adverse effects following therapeutic administration.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, hypertension was reported in 7% of 656 patients receiving cinacalcet compared to 5% of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) QT interval prolongation and ventricular dysrhythmias secondary to the development of hypocalcemia have been reported in patients receiving cinacalcet therapy (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) CASE REPORT: A 66-year-old woman with ESRD on hemodialysis on 30 mg of cinacalcet daily for 2 weeks presented with facial, abdominal and upper extremity twitching for 48 hours and was subsequently found to have a serum calcium of 7.4 mg/dL and prolonged QTc on ECG (Lazar & Stankus, 2007).
    C) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, hypotension was reported in 11.6% of 1938 patients receiving cinacalcet compared to 10.5% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) Isolated cases of hypotension, worsening heart failure, and dysrhythmias have been reported during post-marketing surveillance of cinacalcet, possibly mediated by decreased serum calcium levels, although a definitive causal relationship could not be established (Prod Info SENSIPAR(R) oral tablets, 2014)

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, dyspnea was reported in 13.4% of 1938 patients receiving cinacalcet compared to 11.5% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) In other clinical studies, dyspnea was reported in 18% of cinacalcet patients, as compared to 13% of placebo-treated patients (Lindberg et al, 2003; Franceschini et al, 2003).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, cough was reported in 11.7% of 1938 patients receiving cinacalcet compared to 9.8% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    C) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, upper respiratory tract infection was reported in 7.6% of 1938 patients receiving cinacalcet compared to 6.3% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, dizziness was reported in 10% of 656 patients receiving cinacalcet compared to 8% of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, dizziness was reported in 7.3% of 1938 patients receiving cinacalcet compared to 4.7% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, asthenia was reported in 7% of 656 patients receiving cinacalcet compared to 4% of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, asthenia was reported in 5.4% of 1938 patients receiving cinacalcet compared to 3.8% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, headache was reported in 11.5% of 1938 patients receiving cinacalcet compared to 9.6% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) According to a double-blind placebo-controlled trial of patients with primary hyperparathyroidism, headache was reported in 4 of 33 (12%) patients receiving cinacalcet compared to 2 of 34 (6%) patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    D) SEIZURE
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, seizures were reported in 2.5% of 1938 patients receiving cinacalcet compared to 1.6% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) During other clinical trials, generalized tonic-clonic seizures were reported in 43 of 3049 (1.4%) cinacalcet-treated patients compared to 5 of 687 (0.7%) patients receiving placebo. The threshold for seizure-activity may be reduced in patients who have significantly reduced serum calcium concentrations. In patients with a history of seizure activity, ongoing serum calcium monitoring is recommended (Prod Info SENSIPAR(R) oral tablets, 2014).
    E) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In a small study, paresthesia was reported in 3/16 patients (19%) treated with cinacalcet (Shoback et al, 2003).
    b) Paresthesia along with other symptoms (ie, myalgia, cramping, and tetany) of hypocalcemia may develop in patients with low serum calcium levels as a normal therapeutic response of cinacalcet therapy (Prod Info SENSIPAR(R) oral tablets, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, nausea and vomiting were reported in 31% and 27%, respectively, of 656 patients receiving cinacalcet compared to 19% and 15%, respectively, of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, nausea and vomiting were reported in 29.1% and 25.6%, respectively, of 1938 patients receiving cinacalcet compared to 15.5% and 13.7%, respectively, of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    c) Based on several studies, vomiting occurred much more frequently with cinacalcet therapy as compared to placebo (Quarles et al, 2003).
    d) According to a double-blind placebo-controlled trial of patients with primary hyperparathyroidism, nausea was reported in 10 of 33 (30%) patients receiving cinacalcet compared to 6 of 34 (18%) patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, diarrhea was reported in 21% of 656 patients receiving cinacalcet compared to 20% of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, diarrhea was reported in 20.5% of 1938 patients receiving cinacalcet compared to 18.7% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, abdominal pain and upper abdominal pain were reported in 10.9% and 8.2%, respectively, of 1938 patients receiving cinacalcet compared to 9.6% and 6.3%, respectively, of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, dyspepsia was reported in 7.4% of 1938 patients receiving cinacalcet compared to 4.6% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, anorexia was reported in 6% of 656 patients receiving cinacalcet compared to 4% of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, decreased appetite was reported in 5.96% of 1938 patients receiving cinacalcet compared to 3.5% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    F) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, constipation was reported in 5% of 1938 patients receiving cinacalcet compared to 3.8% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, rash was reported in 2.2% of 1938 patients receiving cinacalcet compared to 1.9% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) Rash was reported during post-marketing surveillance of cinacalcet (Prod Info SENSIPAR(R) oral tablets, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, myalgia was reported in 15% of 656 patients receiving cinacalcet compared to 14% of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) Myalgia was reported during post-marketing surveillance of cinacalcet (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) According to pooled data from 3 double-blind, placebo-controlled short-term studies (up to 6 months) of patients with chronic kidney disease on dialysis, non-cardiac chest pain was reported in 6% of 656 patients receiving cinacalcet compared to 4% of 470 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    C) SKELETAL MUSCLE SPASM
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, muscle spasms were reported in 11.1% of 1938 patients receiving cinacalcet compared to 9.2% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) According to a double-blind placebo-controlled trial of patients with primary hyperparathyroidism, muscle spasms were reported in 6 of 33 (18%) patients receiving cinacalcet compared to 0 patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    D) BACKACHE
    1) WITH THERAPEUTIC USE
    a) According to a double-blind placebo-controlled trial of patients with primary hyperparathyroidism, back pain was reported in 4 of 33 (12%) patients receiving cinacalcet compared to 2 of 34 (6%) patients receiving placebo (Prod Info SENSIPAR(R) oral tablets, 2014).
    E) ADYNAMIC BONE DISEASE
    1) WITH THERAPEUTIC USE
    a) Adynamic bone disease may occur when intact parathyroid hormone (iPTH) levels are suppressed below 100 pg/mL. During a year-long clinical trial that evaluated the bone histomorphometry in patients who were being treated with cinacalcet, 3 patients developed adynamic bone disease. Two of the 3 patients had iPTH levels that were below 100 pg/mL at several points during the study (Prod Info SENSIPAR(R) oral tablets, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) During a randomized, double-blind placebo-controlled long-term clinical trial (up to 64 months) of patients with secondary hyperparathyroidism and chronic kidney disease receiving dialysis, hypersensitivity reactions were reported in 9.4% of 1938 patients receiving cinacalcet compared to 8.3% of 1923 patients receiving placebo. The mean duration of treatment for patients in the cinacalcet group was 21 months (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) Hypersensitivity reactions, including angioedema and urticaria, were reported during post-marketing surveillance of cinacalcet (Prod Info SENSIPAR(R) oral tablets, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Cinacalcet is classified as FDA pregnancy category C. Animal studies have shown maternal toxicities and fetal toxicities with exposure at higher than expected human dose. Cinacalcet is excreted in breast milk in animal studies with a high milk-to-plasma ratio.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: In pregnant rats exposed to the equivalent of up to 4 times that of a 180 mg/day human oral dose, no teratogenicity was observed, but maternal and/or fetal toxicity was reported (Prod Info SENSIPAR(R) oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) PREGNANCY CATEGORY
    1) Cinacalcet is classified as FDA pregnancy category C (Prod Info SENSIPAR(R) oral tablets, 2014).
    C) ANIMAL STUDIES
    1) RATS, RABBITS: In pregnant rats exposed to the equivalent of up to 4 times that of a 180 mg/day human oral dose, no teratogenicity was observed, but maternal and/or fetal toxicity was reported. Maternal toxicity as well as decreased body-weight gain in pups was reported in female rats exposed to up to 3 times that of a 180 mg/day human oral dose during gestation and through lactation. Maternal but not fetal adverse effects were reported in pregnant rabbits with drug exposure less than that expected in humans. Cinacalcet crosses the placental barrier in rabbits (Prod Info SENSIPAR(R) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) BREAST MILK
    a) RATS: Rat studies have shown that cinacalcet is excreted in breast milk with a high milk-to-plasma ratio. However, it is not known if cinacalcet is excreted in human milk. Based on relatively significant adverse effects with cinacalcet, patients should be advised to either discontinue nursing or discontinue the drug (Prod Info SENSIPAR(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility in humans from exposure to this agent (Prod Info SENSIPAR(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) No impairment in fertility was observed in male or female rats at doses of 5 and 25 mg/kg/day (doses were equivalent to exposures up to 3 times those resulting in a human oral dose of 180 mg/kg/day based on AUC comparison) (Prod Info SENSIPAR(R) oral tablets, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS226256-56-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) SUMMARY - Based on standard dietary carcinogenicity bioassays in mice and rats, no increase incidence of tumors was observed with cinacalcet therapy (Prod Info Sensipar(TM), 2004).
    2) Mice were given dietary doses of cinacalcet at 15, 50, 125 mg/kg/day in males and females were given 30, 70, 200 mg/kg/day; and rats were given dietary doses of cinacalcet at 5, 15, 35 mg/kg/day in males and 5, 20, 35 mg/kg/day in females (exposures in both species were equivalent to 2 times that of a human oral dose of 180 mg/day based on AUC comparison) with no increase incidence of tumors evident (Prod Info Sensipar(TM), 2004).

Genotoxicity

    A) Cinacalcet demonstrated no evidence of mutagenicity in a variety of genetic tests.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial serum calcium concentrations. Nadir in serum calcium can occur 8 to 12 hours after a single therapeutic dose.
    B) Institute continuous cardiac monitoring and obtain a baseline ECG to evaluate for evidence of QTc prolongation or dysrhythmias in patients with a significant exposure. Although rare with cinacalcet therapy, QTc prolongation and ventricular dysrhythmias can occur secondary to hypocalcemia.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor vital signs and mental status.
    E) Plasma cinacalcet concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) Monitor serial serum calcium concentrations. The nadir in serum calcium occurs 8 to 12 hours after a single therapeutic dose (Block & Goodman, 2004).
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Plasma cinacalcet concentrations are not readily available or clinically useful in the management of overdose.
    4.1.4) OTHER
    A) OTHER
    1) ECG MONITORING
    a) Institute continuous cardiac monitoring and obtain a baseline ECG to evaluate for evidence of QTc prolongation or dysrhythmias in patients with a significant exposure. Although rare with cinacalcet therapy, QTc prolongation and ventricular dysrhythmias can occur secondary to hypocalcemia (Prod Info SENSIPAR(R) oral tablets, 2014).
    2) MONITORING
    a) Monitor vital signs and mental status.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted. Patients with evidence of severe hypocalcemia (eg, paresthesias, myalgias, tetany, QT interval prolongation, dysrhythmias, seizures) should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent ingestion of 1 or 2 tablets, who remains asymptomatic, can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance, including serial serum calcium concentrations, until they are clearly improving and clinically stable. Nadir in serum calcium occurs 8 to 12 hours after a single therapeutic dose (Block & Goodman, 2004).

Monitoring

    A) Monitor serial serum calcium concentrations. Nadir in serum calcium can occur 8 to 12 hours after a single therapeutic dose.
    B) Institute continuous cardiac monitoring and obtain a baseline ECG to evaluate for evidence of QTc prolongation or dysrhythmias in patients with a significant exposure. Although rare with cinacalcet therapy, QTc prolongation and ventricular dysrhythmias can occur secondary to hypocalcemia.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor vital signs and mental status.
    E) Plasma cinacalcet concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Intravenous administration of calcium gluconate or calcium chloride may be required for significant hypocalcemia. Institute continuous cardiac monitoring and monitor ECG for evidence of QT prolongation or dysrhythmias. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    B) MONITORING OF PATIENT
    1) Monitor serial serum calcium concentrations. Nadir in serum calcium can occur 8 to 12 hours after a single therapeutic dose (Block & Goodman, 2004).
    2) Institute continuous cardiac monitoring and obtain a baseline ECG to evaluate for evidence of QTc prolongation or dysrhythmias in patients with a significant exposure. Although rare with cinacalcet therapy, QTc prolongation and ventricular dysrhythmias can occur secondary to hypocalcemia (Prod Info SENSIPAR(R) oral tablets, 2014).
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Monitor vital signs and mental status.
    5) Plasma cinacalcet concentrations are not readily available or clinically useful in the management of overdose.
    C) HYPOCALCEMIA
    1) Correct hypocalcemia with intravenous CALCIUM CHLORIDE (10% SOLUTION): ADULT 2 to 4 mg/kg (0.02 to 0.04 mL/kg) with repeat doses as necessary. PEDIATRIC: 10 to 30 mg/kg (0.1 to 0.3 mL/kg) infused slowly with repeat doses as necessary. Ideally, repeat doses should be based on measured deficits of ionized calcium. CALCIUM GLUCONATE (10% solution) may also be used, but the dose is 3 times the amount of the dose for calcium chloride.
    D) TORSADES DE POINTES
    1) Obtain an ECG and institute continuous cardiac monitoring in patients with substantial ingestion. Although rare with cinacalcet therapy, QTc prolongation and ventricular dysrhythmias can occur secondary to hypocalcemia (Prod Info SENSIPAR(R) oral tablets, 2014). Primary treatment is correction of hypocalcemia. At the time of this review, torsades de pointes has not been reported.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    E) SEIZURE
    1) Evaluate for electrolyte disturbances (especially hypocalcemia), hypoxia, hypoglycemia and dysrhythmias and correct as necessary. Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbital. Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding (93% to 97%) and large volume of distribution (1000 liters) (Prod Info SENSIPAR(R) oral tablets, 2014).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Doses up to 300 mg/day (titrated) have been tolerated in hemodialysis patients.
    B) THERAPEUTIC DOSE: ADULTS: For secondary hyperparathyroidism, the recommended starting dose is 30 mg daily titrated up to 180 mg once daily as necessary. For the treatment of parathyroid carcinoma or primary hyperparathyroidism, the recommended dose is 30 mg twice daily , titrated up to 90 mg 3 to 4 times daily (270 mg to 360 mg daily) as necessary. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) SECONDARY HYPERPARATHYROIDISM
    a) The recommended starting dose is 30 mg once daily (Prod Info SENSIPAR(R) oral tablets, 2014).
    b) Based on clinical trials, doses required to achieve PTH reduction were variable and most studies used a dose titration phase followed by a constant dose (Franceschini et al, 2003). A dose should NOT be titrated any more frequently, then every 2 to 4 weeks through sequential doses of 30, 60, 90, 120 and 180 mg once daily to target intact parathyroid hormone (iPTH) levels consistent with the NKF-K/DOQI recommendation for chronic kidney disease (CKD) patients on dialysis of 150 to 300 picogram/mL (Prod Info SENSIPAR(R) oral tablets, 2014).
    c) Cinacalcet can be used alone or in combination with vitamin D sterols and/or phosphate binders (Prod Info SENSIPAR(R) oral tablets, 2014).
    2) PARATHYROID CARCINOMA AND PRIMARY HYPERPARATHYROIDISM
    a) The recommended starting dose is 30 mg twice daily. The dose can be titrated every 2 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 needed to normalize serum calcium levels (Prod Info SENSIPAR(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of cinacalcet use in children have not been established (Prod Info SENSIPAR(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) At the time of this review, a specific toxic dose has not been established.
    B) Hemodialysis patients have tolerated doses titrated up to 300 milligrams/day (Prod Info SENSIPAR(R) oral tablets, 2014).

Workplace Standards

    A) ACGIH TLV Values for CAS226256-56-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS226256-56-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS226256-56-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS226256-56-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cinacalcet can increase the sensitivity (modulate) of calcium receptors on the surface of parathyroids cells, and can thereby inhibit the oversecretion of parathyroid hormone, which is a characteristic feature of hyperparathyroidism. Cinacalcet works directly to lower parathyroid levels increasing the sensitivity of the calcium sensing receptor to extracellular calcium. Calcimimetic compounds, like cinacalcet, inhibit the secretion of parathyroid hormone, and thereby cause a decrease in serum calcium levels (Prod Info SENSIPAR(R) oral tablets, 2014; Nemeth et al, 2004; Anon, 2004).

Physicochemical

Physical Characteristics

    A) Cinacalcet hydrochloride is a white to off-white, crystalline solid that is slightly soluble in water and soluble in methanol or 95% ethanol (Prod Info SENSIPAR(R) oral tablets, 2011).

Molecular Weight

    A) BASE: 357.4 (Prod Info SENSIPAR(R) oral tablets, 2011)
    B) HYDROCHLORIDE: 393.9 (Prod Info SENSIPAR(R) oral tablets, 2011)

References

General Bibliography

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    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
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    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
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    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
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