Parsabiv

Contraindications

Known hypersensitivity to etelcalcetide or any of its excipients; hypersensitivity reactions, including pruritic rash, urticaria, and face edema, have occurred

Cautions

Cases of hypotension, congestive heart failure, and decreased myocardial performance reported in clinical trials; closely monitor for worsening signs and symptoms of heart failure

Adynamic bone may develop if PTH levels are chronically suppressed; if PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or etelcalcetide should be reduced or discontinued; after discontinuation, resume therapy at a lower dose to maintain PTH levels in the target range

Rare reports of upper GI bleeding occurred during clinical trials; the exact cause of the GI bleeds were unknown and there were too few cases (2 of 1253 patient-years of exposure) to determine if GI bleeding was related to etelcalcetide

Hypocalcemia

• Etelcalcetide lowers serum calcium and can lead to hypocalcemia, sometimes severe; low serum calcium can cause paresthesias, myalgias, muscle spasms, seizures, QT interval prolongation, and ventricular arrhythmia
• Patients predisposed to QT interval prolongation, ventricular arrhythmias, and seizures are at increased risk of hypocalcemia and should be monitored closely; patients should be educated about the symptoms of hypocalcemia and should be advised to contact a healthcare provider if it occurs
• Measure corrected serum calcium prior to initiation, within 1 week after initiation or dose adjustment, and then every 4 weeks (see Administration for dose adjustment)

Mechanism of Action

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

Distribution

Protein bound: Predominately bound to plasma albumin by reversible covalent binding

Blood to plasma ratio: ~0.6

Vd: 796 L

Metabolism

Biotransformed in blood by reversible disulfide exchange with endogenous thiols to predominantly form conjugates with serum albumin

Not metabolized by CYP450 enzymes

Elimination

Half-life: 3-4 days

Excretion

• Normal renal function (volunteers in clinical trials): Cleared by renal excretion
• Hemodialysis: Removed with a hemodialysis clearance value of 7.66 L/hr

PARSABIV (etelcalcetide) is a synthetic peptide calcium-sensing receptor agonist. Etelcalcetide is a white to off-white powder with a molecular formula of C38H73N21O10S2•xHCl(4 ≤ x ≤ 5) and a molecular weight of 1047.5 g/mol (monoisotopic; free base). It is soluble in water. The hydrochloride salt of etelcalcetide is described chemically as N-acetyl-D-cysteinyl-S-(L-cysteine disulfide)-D-alanyl-D-arginyl-D-arginyl-D-arginylD-alanyl-D-argininamide, hydrochloride.

PARSABIV (etelcalcetide) injection is supplied in a single-dose vial containing 5 mg/mL of etelcalcetide as a sterile, preservative-free, ready-to-use clear and colorless solution for intravenous injection. Each PARSABIV single-dose vial contains 2.5 mg etelcalcetide (equivalent to 2.88 mg etelcalcetide as hydrochloride salt) or 5 mg etelcalcetide (equivalent to 5.77 mg etelcalcetide as hydrochloride salt) or 10 mg etelcalcetide (equivalent to 11.54 mg etelcalcetide as hydrochloride salt). PARSABIV single-dose vial is formulated with 0.85% (w/v) sodium chloride, 10 mM succinic acid, and adjusted to pH 3.3 with sodium hydroxide and/or hydrochloric acid.

Before taking Parsabiv, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Parsabiv or to any of its ingredients
• are taking Sensipar. You cannot be on both drugs at the same time. When switching from Sensipar to Parsabiv, you should stop taking Sensipar for at least 7 days before starting Parsabiv.
• have or have had heart rhythm problems or heart failure or if you take medicines that can cause heart rhythm problems
• are taking medication to prevent seizures or have had seizures in the past
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed 

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. 

Calcimimetic agent; binds to and increases sensitivity of calcium-sensing receptors on parathyroid glands to extracellular calcium, resulting in reduced serum parathyroid hormone (PTH) and calcium concentrations.1 2 3 4 6

Administration

IV Administration

Administer by direct (“bolus”) IV injection into the venous line of the dialysis circuit during the rinse-back procedure at the end of hemodialysis or IV after completion of the rinse-back procedure.1

Administer only at the end of hemodialysis sessions.1 If a regularly scheduled hemodialysis session is missed, do not administer the missed dose.1 (See Dosage under Dosage and Administration.)

Do not admix with any other solutions or dilute prior to administration.1

Dosage

Available as etelcalcetide hydrochloride; dosage expressed in terms of etelcalcetide.1

Adults

Initially, 5 mg 3 times weekly.1

In patients being switched from cinacalcet to etelcalcetide, allow ≥7 days to elapse between discontinuance of cinacalcet and initiation of etelcalcetide; use initial etelcalcetide dose of 5 mg.1

Do not initiate etelcalcetide, increase dosage, or reinitiate following an interruption in therapy if albumin-corrected serum calcium concentration is below the lower limit of normal (LLN).1

Titrate dosage to achieve a maintenance dosage within the range of 2.5–15 mg 3 times weekly that maintains PTH concentration within the recommended target range and albumin-corrected serum calcium concentration within the normal range.1

Mean dosage in clinical trials was 7.2 mg 3 times weekly; patients with lower baseline PTH concentrations received lower average dosages.1

Measure albumin-corrected serum calcium concentration 1 week following initiation or subsequent dosage adjustment and every 4 weeks during maintenance therapy.1 Measure PTH concentration 4 weeks following initiation or subsequent dosage adjustment and according to standard practice during maintenance therapy.1

If albumin-corrected serum calcium concentration is within the normal range and PTH concentration is above the recommended target range, increase dosage in 2.5- or 5-mg increments no more frequently than every 4 weeks based on PTH concentration.1

If PTH concentration is below target range, reduce dosage or withhold drug.1 If albumin-corrected serum calcium concentration is less than LLN but ≥7.5 mg/dL and there are no manifestations of hypocalcemia, consider reducing or withholding etelcalcetide or using concomitant therapies to increase albumin-corrected serum calcium.1 If withheld, reinitiate etelcalcetide at a lower dosage when PTH returns to target range and hypocalcemia is corrected.1

If albumin-corrected serum calcium concentration is <7.5 mg/dL or if manifestations of hypocalcemia occur, withhold drug and treat hypocalcemia.1 Reinitiate at a dose 5 mg lower than the last administered dose (or 2.5 mg if the last administered dose was 2.5 or 5 mg) once albumin-corrected serum calcium concentration has returned to normal, manifestations of hypocalcemia have resolved, and predisposing factors for hypocalcemia have been addressed.1

If a regularly scheduled hemodialysis session is missed, do not administer the missed dose.1 Resume therapy at the prescribed dosage with the next scheduled hemodialysis session.1 If doses are missed for >2 weeks, reinitiate at the recommended initial dose of 5 mg (or 2.5 mg if that was the patient's last dose).1

Prescribing Limits

Adults

Maximum 15 mg 3 times weekly.1

Special Populations

No special population dosage recommendations at this time.1

Not a substrate nor an inhibitor or inducer of CYP isoenzymes.1

Not a substrate nor an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporters (OAT) 1 and 3, organic anion transport proteins (OATP) 1B1 and 1B3, and organic cation transporter (OCT) 2; not a substrate of peptide transporters (PEPT) 1 and 2; and not an inhibitor of bile salt export pump (BSEP).1

Specific Drugs

      Recommended Dosing

• Ensure corrected serum calcium is at or above the lower limit of normal prior to Parsabiv initiation, a Parsabiv dose increase, or re-initiation of Parsabiv therapy after a dosing interruption [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].
  
• The recommended starting dose of Parsabiv is 5 mg administered by intravenous (IV) bolus injection three times per week at the end of hemodialysis treatment.
  
• The maintenance dose of Parsabiv is individualized and determined by titration based on parathyroid hormone (PTH) and corrected serum calcium response [see Dosage and Administration (2.2)]. The maintenance dose is the dose that maintains PTH levels within the recommended target range and corrected serum calcium within the normal range. The lowest maintenance dose of Parsabiv is 2.5 mg three times per week, and the highest maintenance dose of Parsabiv is 15 mg three times per week.
  
• Administer Parsabiv only at the end of hemodialysis treatment.  
  
• If a regularly scheduled hemodialysis treatment is missed, DO NOT administer any missed doses. Resume Parsabiv at the end of the next hemodialysis treatment at the prescribed dose. If doses of Parsabiv are missed for more than 2 weeks, re-initiate Parsabiv at the recommended starting dose of 5 mg (or 2.5 mg if that was the patient’s last dose).

      Monitoring and Dose Adjustment

• Monitor corrected serum calcium and PTH levels during dose initiation, dose adjustment, and dose maintenance according to the schedule in Table 1.

• Titrate Parsabiv dose based on PTH and corrected serum calcium response. At the maintenance dose, PTH levels should be within the recommended target range and corrected serum calcium within the normal range.
  
• Increase the dose of Parsabiv in 2.5 mg or 5 mg increments in individuals with corrected serum calcium within the normal range and PTH levels above the recommended target range based on the patient’s PTH levels no more frequently than every 4 weeks up to a maximum dose of 15 mg three times per week.
  
• Decrease or temporarily discontinue Parsabiv dosing in individuals with PTH levels below the target range. In individuals with a corrected serum calcium below the lower limit of normal but at or above 7.5 mg/dL without symptoms of hypocalcemia, consider decreasing or temporarily discontinuing Parsabiv or use concomitant therapies to increase corrected serum calcium [see Warnings and Precautions (5.1)]. If the dose is stopped, then re-initiate Parsabiv at a lower dose when the PTH is within the target range and hypocalcemia has been corrected.
  
• Stop Parsabiv and treat hypocalcemia if the corrected serum calcium falls below 7.5 mg/dL or patients report symptoms of hypocalcemia [see Warnings and Precautions (5.1)]. When the corrected serum calcium is within normal limits, symptoms of hypocalcemia have resolved, and predisposing factors for hypocalcemia have been addressed, re-initiate Parsabiv at a dose 5 mg lower than the last administered dose. If the last administered dose of Parsabiv was 2.5 mg or 5 mg, re-initiate at a dose of 2.5 mg.

      Administration

• Do not mix or dilute Parsabiv prior to administration. The solution is clear and colorless. Inspect Parsabiv for particulate matter and discoloration prior to administration. Do not use Parsabiv vials if particulate matter or discoloration is observed.
  
• Administer Parsabiv 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.

      Switching from Cinacalcet to Parsabiv

• Discontinue cinacalcet for at least 7 days prior to starting Parsabiv, and initiate Parsabiv treatment at a starting dose of 5 mg. Ensure corrected serum calcium is at or above the lower limit of normal prior to Parsabiv initiation [see Warnings and Precautions (5.1)].

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)].

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of low calcium levels like muscle cramps or spasms, numbness and tingling, or seizures.
• A heartbeat that does not feel normal.
• Very bad dizziness or passing out.
• Very upset stomach or throwing up.
• Very bad belly pain.
• Black, tarry, or bloody stools.
• Throwing up blood or throw up that looks like coffee grounds.
• Heart failure has happened with Parsabiv, as well as heart failure that has gotten worse in people who already have it. Tell your doctor if you have heart disease. Call your doctor right away if you have shortness of breath, a big weight gain, a heartbeat that is not normal, or swelling in the arms or legs that is new or worse.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Upset stomach or throwing up.
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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

Parsabiv is used to treat overactive parathyroid gland (hyperparathyroidism) in adults with chronic kidney failure who are on dialysis.

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

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

Etelcalcetide is used to treat overactive parathyroid gland (hyperparathyroidism) in adults with chronic kidney failure who are on dialysis.

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

Before you receive etelcalcetide, tell your doctor if you have taken cinacalcet within the past 7 days.

You should not be treated with etelcalcetide if you are allergic to it.

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

• congestive heart failure;
• stomach or intestinal bleeding;
• a seizure;
• long QT syndrome (in you or a family member); or
• if you have used cinacalcet (Sensipar) within the past 7 days.

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 etelcalcetide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.BasicDescription Back to TopParsabiv Side Effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• a seizure (convulsions);
• shortness of breath (even with mild exertion), swelling, rapid weight gain;
• irregular heartbeats;
• low calcium levels--muscle spasms or contractions, numbness or tingly feeling (around your mouth, or in your fingers and toes); or
• signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.

Common side effects may include:

• numbness or tingling;
• muscle spasms;
• low calcium;
• headache; or
• nausea, vomiting, diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.