KENGREAL (Page 2 of 4)

7 DRUG INTERACTIONS

7.1 Thienopyridines

Clopidogrel or prasugrel administered during KENGREAL infusion will have no antiplatelet effect until the next dose is administered. Therefore, administer clopidogrel or prasugrel after KENGREAL infusion is discontinued [see Dosage and Administration (2.2) and Clinical Pharmacology ( 12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on cangrelor use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated myocardial infarction can be fatal to the pregnant women and fetus (see Clinical Considerations).

In animal reproduction studies, continuous infusion of cangrelor in pregnant rats and rabbits throughout organogenesis at dose approximately 2-times the maximum recommended human dose (MRHD) did not result in fetal malformations (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Myocardial infarction is a medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of cangrelor on the fetus.

Labor or delivery

Cangrelor use during labor and delivery may increase the risk for maternal bleeding and hemorrhage. Performance of neuraxial blockade procedures is not advised during cangrelor use due to potential risk of spinal hematoma. When possible, discontinue cangrelor 1 hour prior to labor, delivery, or neuraxial blockade [see Clinical Pharmacology (12.2)].

Data

Animal Data

A prenatal and postnatal development study in female rats demonstrated a slight increase in the incidence of maternal mortality in dams treated at doses up to 30 mcg/kg/min (approximately 7.5 times the MRHD) cangrelor continuous infusion from Day 6 of gestation up to Day 23 post-partum. Pregnancy rates, gestation index, length of gestation, numbers of live, dead and malformed pups, sex ratio, live birth index, and lactation of the maternal animals were unaffected.

Cangrelor administered at dose levels of ≥ 3 mcg/kg/min in pregnant rats from Day 6 to 17 post-coitum resulted in dose-related fetal growth retardation characterized by increased incidences of incomplete ossification and unossified hind limb metatarsals.

An embryo-fetal development study in rabbits administered 4, 12, or 36 mcg/kg/min cangrelor continuous IV infusion from Day 6 to Day 19 post-coitum resulted in increased incidences of abortion and intrauterine losses at ≥12 mcg/kg/min (3 times the MRHD). Fetal growth retardation occurred at 36 mcg/kg/min (9 times the MRHD) and was characterized by decreased fetal weights, slight reduction in ossification, and a slight increase in skeletal variants.

Cangrelor did not produce malformations in either the rat or rabbit embryo-fetal development studies and is not considered to be a teratogen.

8.2 Lactation

Risk Summary

There are no data on the presence of cangrelor in human milk or animal milk, the effects on the breastfed infant, or the effects on milk production. However, due to its short-half life, cangrelor exposure is expected to be very low in the breastfed infant.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

In CHAMPION PHOENIX, 18% of patients were ≥75 years. No overall differences in safety or effectiveness were observed between these patients and those patients <75 years [see Clinical Studies ( 14.1)].

8.6 Renal Impairment

No dosage adjustment is required for patients with mild, moderate, or severe renal impairment [see Clinical Pharmacology ( 12.3)].

8.7 Hepatic Impairment

KENGREAL has not been studied in patients with hepatic impairment. However, the metabolism of KENGREAL is not dependent of hepatic function, so dosage adjustment is not required for patients with hepatic impairment [see Clinical Pharmacology ( 12.3)].

10 OVERDOSAGE

There is no specific treatment to reverse the antiplatelet effect of KENGREAL but the effect is gone within one hour after the drug is discontinued.

In clinical trials, 36 patients received an overdose of KENGREAL, ranging from 36 to 300 mcg/kg (bolus dose) or 4.8 to 13.7 mcg/kg/min (infusion dose). The maximum overdose received was 10 times the PCI bolus dose or 3.5 times the PCI infusion dose in 4 patients. No clinical sequela were noted as a result of overdose following completion of KENGREAL therapy.

11 DESCRIPTION

KENGREAL is a direct-acting P2Y12 platelet receptor inhibitor that blocks adenosine diphosphate (ADP)-induced platelet activation and aggregation. The chemical structure is similar to adenosine triphosphate (ATP).

The chemical name of KENGREAL is tetrasodium salt of N6-[2-(methylthio)ethyl]-2-[(3,3,3,-trifluoropropyl)-5’-adenylic acid, monanhydride with (dichloromethylene) bisphosphonic acid.

The empirical formula of KENGREAL is C17 H21 N5 Cl2 F3 Na4 O12 P3 S2 and the molecular weight is 864.3 g/mol.

The chemical structure is represented below:

chemical structure
(click image for full-size original)

Cangrelor for Injection is a sterile white to off-white lyophilized powder for IV infusion. In addition to the active ingredient, cangrelor, each single use vial contains mannitol (158 mg), sorbitol (52 mg), and sodium hydroxide to adjust the pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cangrelor is a direct P2Y12 platelet receptor inhibitor that blocks ADP-induced platelet activation and aggregation. Cangrelor binds selectively and reversibly to the P2Y12 receptor to prevent further signaling and platelet activation.

12.2 Pharmacodynamics

Cangrelor inhibits activation and aggregation of platelets. After administration of a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min IV infusion, platelet inhibition occurs within 2 minutes.

Figure 2 shows the effect on platelet activity, and its relation to cangrelor plasma concentration, of administering a 30 mcg/kg IV bolus, followed by a 1-hour 4 mcg/kg/min IV infusion, of cangrelor. The anti-platelet effect is maintained for the duration of the infusion. After discontinuation of the infusion, the anti-platelet effect decreases rapidly and platelet function returns to normal within 1 hour.

Figure 2 : Cangrelor PD Characteristics

Figure 2: Cangrelor PD Characteristics
(click image for full-size original)

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