Drug Interactions

In Vitro Assessment of Drug Interactions

Etelcalcetide did not inhibit or induce CYP450 enzymes, and is not a substrate

 of CYP450 enzymes.

 

 Etelcalcetide was not a substrate of efflux and uptake transporter proteins

 (P-glycoprotein [Pgp], breast cancer resistance protein [BCRP], 

organic anion transporter [OAT] 1 and 3, organic anion polypeptide 

transporter [OATP] 1B1 and 1B3, organic cation transporter [OCT] 2, 

and peptide transporter [PEPT] 1 and 2).

 

Etelcalcetide was also not an inhibitor of common transporter proteins 

(Pgp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or bile salt export pump [BSEP]).

BRIEF SUMMARY

 

ETELCALCETIDE- (Feb 2017)

 

Indn-      To treat secondary hyperparathyroidism  in adult patients  with chronic kidney disease dialysis

 

Comp-       Injection: 2.5 mg/0.5 mL solution in a single-dose vial 

 Injection: 5 mg/mL solution in a single-dose vial 

 Injection: 10 mg/2 mL solution in a single-dose vial PARSABIV is a calcium-sensing receptor agonist indicated for:

 Secondary hyperparathyroidism (HPT) in adult patients with 

chronic kidney disease (CKD) on hemodialysis. 

 

 

ADR-    The most common adverse reactions (. 5%) were blood calcium decreased, 

muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, 

and paresthesiaPARSABIV is contraindicated in patients with known hypersensitivity 

to etelcalcetide or any of its excipients. 

 

WARNINGS AND PRECAUTIONS

 

1. Hypocalcemia Sometimes severe. Severe hypocalcemia can cause 

 paresthesias, myalgias, muscle spasms, seizures, QT prolongation,

 and ventricular arrhythmias. . 

 

CI-      PARSABIV is contraindicated in patients with known hypersensitivity 

to etelcalcetide or any of its excipients. 

 

WARNINGS-

 

1. Hypocalcemia Sometimes severe. Severe hypocalcemia can cause 

 paresthesias, myalgias, muscle spasms, seizures, QT prolongation,

 and ventricular arrhythmias. 

 

Pat Infn-

Hypocalcemia

Advise patients to report symptoms of hypocalcemia, including paresthesias, 

myalgias, muscle spasms, and seizures, to their healthcare provider

 

Heart Failure

Advise patients with heart failure that use of PARSABIV may worsen 

their heart failure and additional monitoring may be required 

 

 

 

 

===============================================================

 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-2

  

Name of the  Drug-         PARSABIV

 

Active Ingredient-           Etecalcetide                                                                                                                                                                                                         Pharmacological Classification- 

 

                       To treat secondary hyperparathyroidism  in adult patients

                       with chronic kidney disease dialysis

                                                                                                                           

Date of Approval-          02-08-2017

 

 (Ref- FDA approved List 2017)

 

HIGHLIGHTS OF PRESCRIBING INFORMATION 

These highlights do not include all the information needed to use

 PARSABIV safely and effectively. 

See full prescribing information for PARSABIV.

 

PARSABIV. (etelcalcetide) injection, for intravenous use 

Initial U.S. Approval: 2017

 

                                                                                                                                               INDICATIONS AND USAGE

 

PARSABIV is a calcium-sensing receptor agonist indicated for:

 Secondary hyperparathyroidism (HPT) in adult patients with 

chronic kidney disease (CKD) on hemodialysis.                                                                                                                                                                                                                                                                    

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

ADVERSE REACTIONS

 

The most common adverse reactions (. 5%) were blood calcium decreased, 

muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, 

and paresthesia. 

 

CONTRAINDICATIONS

 

PARSABIV is contraindicated in patients with known hypersensitivity 

to etelcalcetide or any of its excipients. 

 

WARNINGS AND PRECAUTIONS

 

1. Hypocalcemia Sometimes severe. Severe hypocalcemia can cause 

 paresthesias, myalgias, muscle spasms, seizures, QT prolongation,

 and ventricular arrhythmias. 

 

2. Patients predisposed to QT interval prolongation, ventricular arrhythmias, 

  and seizures may be at increased risk and require close monitoring. 

 

3. Educate patients on the symptoms of hypocalcemia and advise them to

 contact a healthcare provider if they occur. 

 

4. Worsening Heart Failure Reductions in corrected serum calcium may be 

 associated with congestive heart failure, however, a causal relationship 

 to PARSABIV could not be completely excluded. 

 

5.Closely monitor patients for worsening signs and symptoms of heart failure. 

 

5. Upper Gastrointestinal (GI) Bleeding Patients with risk factors for upper 

 GI bleeding may be at increased risk. Monitor patients and promptly evaluate 

 and treat any suspected GI bleeding. 

 

6.  Adynamic Bone May develop if PTH levels are chronically suppressed.

  If PTH levels decrease below the recommended target range, the dose

  of PARSABIV should be reduced or discontinued. 

 

 

INDICATIONS AND USAGE

 

PARSABIV is a calcium-sensing receptor agonist indicated for:

 Secondary hyperparathyroidism (HPT) in adult patients with 

chronic kidney disease (CKD) on hemodialysis. 

 

Limitations of Use:

PARSABIV has not been studied in adult patients with parathyroid carcinoma,

primary hyperparathyroidism, or with CKD who are not on hemodialysis and is not

recommended for use in these populations.

 

DOSAGE AND ADMINISTRATION

 

1.Ensure corrected serum calcium is at or above the lower limit of normal prior

 to initiation, dose increase, or re-initiation. 

 

2.The recommended starting dose is 5 mg administered by intravenous

 bolus injection three times per week at the end of hemodialysis treatment. 

 

3.The maintenance dose is individualized and determined by titration

 based on parathyroid hormone (PTH) and corrected serum 

 calcium response.

 The dose range is 2.5 to 15 mg three times per week. 

 

4.The dose may be increased in 2.5 mg or 5 mg increments no more 

frequently than every 4 weeks. 

 

5.Measure serum calcium within 1 week after initiation or dose adjustment 

and every 4 weeks for maintenance. 

 

6.Measure PTH after 4 weeks from initiation or dose adjustment. 

 

7.Decrease or temporarily discontinue PARSABIV, in individuals with PTH

levels below the target range. 

 

8. Consider decreasing or temporarily discontinuing PARSABIV or use 

concomitant therapies to increase corrected serum calcium in patients 

with a corrected serum calcium below the lower limit of normal but at or above

7.5 mg/dL without symptoms of hypocalcemia.

 

9. Stop PARSABIV and treat hypocalcemia if the corrected serum calcium falls

below 7.5 mg/dL or patients report symptoms of hypocalcemia. 

 

10.Do not mix or dilute prior to administration. 

 

11.Administer by intravenous bolus injection into the venous line of the dialysis

circuit at the end of the hemodialysis treatment during rinse back 

or intravenously after rinse back. 

 

DOSAGE FORMS AND STRENGTHS

 

 Injection: 2.5 mg/0.5 mL solution in a single-dose vial 

 Injection: 5 mg/mL solution in a single-dose vial 

 Injection: 10 mg/2 mL solution in a single-dose vial 

 

 

PATIENT COUNSELING INFORMATION

 

Hypocalcemia

Advise patients to report symptoms of hypocalcemia, including paresthesias, 

myalgias, muscle spasms, and seizures, to their healthcare provider

 

Heart Failure

Advise patients with heart failure that use of PARSABIV may worsen 

their heart failure and additional monitoring may be required 

 

Upper Gastrointestinal Bleeding Advise patients to report any symptoms 

of upper gastrointestinal bleeding to their health care provider

 

Laboratory Monitoring

Inform patients of the importance of regular blood tests, in order

 to monitor the safety and efficacy of PARSABIV therapy.

 

Lactation -Advise women that use of PARSABIV is not recommended 

while breastfeeding 

 

PARSABIV (etelcalcetide)

 

 

Manufactured for:

KAI Pharmaceuticals, Inc., a wholly owned subsidiary of Amgen, Inc.

One Amgen Center Drive

Thousand Oaks, California 91320-1799

Patent: http://pat.amgen.com/Parsabiv/

c 2017 Amgen, Inc. All rights reserved.

 

 CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

 Etelcalcetide is a calcimimetic agent that allosterically modulates 

 the calcium-sensing receptor (CaSR). Etelcalcetide binds to the CaSR and 

 enhances activation of the receptor by extracellular calcium. 

 

 Activation of the CaSR on parathyroid chief cells decreases PTH secretion.

 

2. Pharmacodynamics

 Following a single intravenous bolus administration of etelcalcetide,

 PTH levels decreased within 30 minutes post dose. In the single-dose study, 

 the extent and duration of the reduction in PTH increased with increasing dose. 

 

 The effect of reducing PTH levels was maintained throughout the 6-month dosing

 period when etelcalcetide was administered by intravenous bolus three times a week.

 

3. Pharmacokinetics

The pharmacokinetics of etelcalcetide is linear and does not change over time

 following single (5 to 60 mg) and multiple intravenous doses (2.5 to 20 mg) 

 in chronic kidney disease patients with secondary hyperparathyroidism

 requiring hemodialysis. 

 

 Etelcalcetide exhibited tri-exponential decay following intravenous administration. 

 

 Based on population pharmacokinetic analysis, following three times a week

 intravenous dosing at the end of each 3- to 6-hour hemodialysis session

 in chronic kidney disease patients, etelcalcetide plasma levels reached

 steady state in 7-8 weeks after dosing with a predicted accumulation ratio 

of 3- to 4-fold, and the effective half-life was 3 to 4 days.

USE IN SPECIFIC POPULATIONS

 

1 Pregnancy

Risk Summary

There are no available data on the use of PARSABIV in pregnant women.

 

The estimated background risk of major birth defects and miscarriage 

for the indicated population is unknown. 

 

In the U.S. general population, the estimated background risk of major birth defects

 and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

 

2. Lactation

Risk Summary

There are no data regarding the presence of PARSABIV in human milk or effects 

on the breastfed infant or on milk production. 

 

Studies in rats showed [14C]-etelcalcetide was present in the milk at concentrations

 similar to plasma. 

 

Because of the potential for PARSABIV to cause adverse effects

 in breastfed infants including hypocalcemia, advise women that use of PARSABIV 

is not recommended while breastfeeding.

 

3.Pediatric Use

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

 

4. Geriatric Use

 Of the 503 patients in placebo-controlled studies who received PARSABIV, 

  177 patients (35.2%) were . 65 years old and 72 patients (14%) were 

. 75 years old. 

 

  No clinically significant differences in safety or efficacy were  observed

   between patients . 65 years and younger patients   (. 18 and < 65 years old). 

  

  No differences in plasma concentrations of   etelcalcetide were observed

   between patients . 65 years and younger patients (. 18 and < 65 years old).

 

 OVERDOSAGE

 There is no clinical experience with PARSABIV overdosage. 

  Overdosage of PARSABIV may lead to hypocalcemia with or without clinical

 symptoms and may require treatment. 

 

  Although PARSABIV is cleared by dialysis, hemodialysis has not been studied

   as a treatment for PARSABIV overdosage. 

 

  In the event of overdosage, corrected serum calcium should be checked and

   patients should be monitored for symptoms of hypocalcemia, and appropriate

 measures should be taken [see Warnings and Precautions (5.1)].