Cangrelor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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Overview
Cangrelor is a P2Y12 platelet inhibitor that is FDA approved for the prevention of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients in who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor and undergoing percutaneous coronary intervention (PCI). Common adverse reactions include bleeding.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Cangrelor is indicated as an adjunct to percutaneous coronary intervention (PCI) to reduce the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.
- *Recommended Dosing
The recommended dosage of Cangrelor is a 30 mcg/kg IV bolus followed immediately by a 4 mcg/kg/min IV infusion. Initiate the bolus infusion prior to PCI. The maintenance infusion should ordinarily be continued for at least 2 hours or for the duration of PCI, whichever is longer.
- Transitioning Patients to Oral P2Y12 Therapy
To maintain platelet inhibition after discontinuation of Cangrelor infusion, an oral P2Y12 platelet inhibitor should be administered. Administer one as described below:
- Ticagrelor: 180 mg at any time during Cangrelor infusion or immediately after discontinuation.
- Prasugrel: 60 mg immediately after discontinuation of Cangrelor. Do not administer prasugrel prior to discontinuation of Cangrelor.
- Clopidogrel: 600 mg immediately after discontinuation of Cangrelor. Do not administer clopidogrel prior to discontinuation of Cangrelor.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
Off-Label Use and Dosage (Pediatric)
Contraindications
Significant Active Bleeding
Cangrelor is contraindicated in patients with significant active bleeding.
Hypersensitivity
Cangrelor is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to Cangrelor or any component of the product.
Warnings
Bleeding
Drugs that inhibit platelet P2Y12 function, including Cangrelor, increase the risk of bleeding.
In CHAMPION PHOENIX bleeding events of all severities were more common with Cangrelor than with clopidogrel. Bleeding complications with Cangrelor were consistent across a variety of clinically important subgroups (see Figure 1).
Once Cangrelor is discontinued, there is no antiplatelet effect after an hour.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Cangrelor has been evaluated in 13,301 subjects in controlled trials, in whom, 5,529 were in the CHAMPION PHOENIX trial.
There was a greater incidence of bleeding with Cangrelor than with clopidogrel. No baseline demographic factor altered the relative risk of bleeding with Cangrelor (see Table 1 and Figure 1).
- Table 1: Major Bleeding Results in the CHAMPION PHOENIX Study (Non-CABG related Bleeding)(a)
KENGREAL: Cangrelor's Brand name
- Figure 1:Bleeding Results in the CHAMPION PHOENIX Study(a) (All Non-CABG related)
KENGREAL: Cangrelor's Brand name
Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified (patient presentation and weight were not pre-specified subgroups). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
Drug Discontinuation
In CHAMPION PHOENIX the rate of discontinuation for bleeding events was 0.3% for Cangrelor and 0.1% for clopidogrel. Discontinuation for non-bleeding adverse events was low and similar for Cangrelor (0.6%) and for clopidogrel (0.4%). Coronary artery dissection, coronary artery perforation, and dyspnea were the most frequent events leading to discontinuation in patients treated with Cangrelor.
Non-Bleeding Adverse Reactions
Serious cases of hypersensitivity were more frequent with Cangrelor (7/13301) than with control (2/12861). These included anaphylactic reactions, anaphylactic shock, bronchospasm, angioedema, and stridor.
- Decreased renal function
Worsening renal function was reported in 3.2% of Cangrelor patients with severe renal impairment (creatinine clearance <30 mL/min) compared to 1.4% of clopidogrel patients with severe renal impairment.
Dyspnea was reported more frequently in patients treated with Cangrelor (1.3%) than with control (0.4%).
Postmarketing Experience
There is limited information regarding Cangrelor Postmarketing Experience in the drug label.
Drug Interactions
Thienopyridines
If clopidogrel or prasugrel are administered during Cangrelor infusion, they will have no antiplatelet effect until the next dose is administered. Clopidogrel and prasugrel, therefore, should not be administered until Cangrelor infusion is discontinued.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C . There are no adequate and well-controlled studies of Cangrelor in pregnant women.
Cangrelor did not produce malformations in either the rat or rabbit reproductive studies, and is not considered to be a teratogen.
In embryo-fetal development studies in rats, Cangrelor produced dose-related fetal growth retardation characterized by increased incidences of incomplete ossification and unossified hind limb metatarsals at plasma concentration of approximately 5 times lower than that achieved in the PCI setting at the maximum recommended human dose (MRHD). In rabbits, Cangrelor was associated with increased incidences of abortion and intrauterine losses, as well as fetal growth retardation at plasma concentrations of approximately 12 times higher than the PCI setting at the MRHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cangrelor in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Cangrelor during labor and delivery.
Nursing Mothers
It is not known whether Cangrelor is excreted in human milk.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic 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.
Gender
There is no FDA guidance on the use of Cangrelor with respect to specific gender populations.
Race
There is no FDA guidance on the use of Cangrelor with respect to specific racial populations.
Renal Impairment
No dosage adjustment is required for patients with mild, moderate, or severe renal impairment.
Hepatic Impairment
Cangrelor has not been studied in patients with hepatic impairment. However, the metabolism of Cangrelor is not dependent of hepatic function, so that dosage adjustment is not required for patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cangrelor in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Cangrelor in patients who are immunocompromised.
Administration and Monitoring
Administration
Cangrelor is intended for IV administration, after reconstitution and dilution.
Preparation
For each 50 mg/vial, reconstitute by adding 5 mL of Sterile Water for Injection. Swirl gently until all material is dissolved. Avoid vigorous mixing. Allow any foam to settle. Ensure that the contents of the vial are fully dissolved and the reconstituted material is a clear, colorless to pale yellow solution. Reconstitute the vial prior to dilution in a bag. Parenteral drug products should be inspected visually for particulate matter after reconstitution.
Do not use without dilution. Before administration, each reconstituted vial must be diluted further with Normal Saline (Sodium Chloride Injection 0.9% USP) or 5% Dextrose Injection USP.
Withdraw the contents from one reconstituted vial and add to one 250 mL saline bag. Mix the bag thoroughly. This dilution will result in a concentration of 200 mcg/mL and should be sufficient for at least 2 hours of dosing. Patients 100 kg and over will require a minimum of 2 bags.
Reconstituted Cangrelor should be diluted immediately. Diluted Cangrelor is stable for up to 12 hours in 5% Dextrose Injection and 24 hours in Normal Saline at Room Temperature. Discard any unused portion of reconstituted solution remaining in the vial.
Administration
Administer Cangrelor via a dedicated IV line.
Administer the bolus volume rapidly (<1 minute), from the diluted bag via manual IV push or pump. Ensure the bolus is completely administered before the start of PCI. Start the infusion immediately after administration of the bolus.
Monitoring
There is limited information regarding Cangrelor Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Cangrelor and IV administrations.
Overdosage
There is no specific treatment to reverse the antiplatelet effect of Cangrelor but the effect is gone within one hour after the drug is discontinued.
In clinical trials, 36 patients received an overdose of Cangrelor, 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 Cangrelor therapy.
Pharmacology
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.
Structure
There is limited information regarding Cangrelor Structure in the drug label.
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
Pharmacokinetics
Cangrelor administered intravenously has linear pharmacokinetics in both healthy volunteers and patients. Cangrelor is rapidly distributed and metabolized, reaching Cmax within 2 minutes after administration of an intravenous bolus followed by infusion.
In a study in healthy volunteers, Cangrelor administration at a dose of 30 mcg/kg bolus plus 4 mcg/kg/min showed a volume of distribution of 3.9 L. Plasma protein binding of Cangrelor is about 97-98%.
Cangrelor is deactivated rapidly in the circulation by dephosphorylation to its primary metabolite, a nucleoside, which has negligible anti-platelet activity. Cangrelor’s metabolism is independent of hepatic function and it does not interfere with other drugs metabolized by hepatic enzymes.
- Elimination
Following IV administration of [3H] Cangrelor 58% of radioactivity was recovered in urine. The remaining 35% of radioactivity was in feces, presumably following biliary excretion. The average elimination half-life of Cangrelor is about 3-6 minutes.
- Specific Populations
Cangrelor pharmacokinetics are not affected by sex, age, renal status or hepatic function. No dose adjustment is needed for these factors.
- Weight
Although weight was a significant covariate for PK with higher clearance in heavier patients, the impact of weight on drug exposure is accounted by the use of weight-based dosing.
- Drug-Drug Interactions
Co-administration of Cangrelor with unfractionated heparin, aspirin, and nitroglycerin was formally studied in healthy subjects, with no evidence of an effect on the PK/PD of Cangrelor.
In clinical trials Cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions.
The expected antiplatelet effect of a 600 mg loading dose of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel or prasugrel was administered during a Cangrelor infusion.
In contrast, the antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during Cangrelor infusion.
- Figure 3: Inhibition (Mean) of 20 µM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Cangrelor 30 mcg/kg Bolus and 120-minute 4 mcg/kg Infusion with Transition to Other Oral P2Y12 Platelet Inhibitors.
As shown in Figure 3, discontinuation of Cangrelor infusion, followed by administration of the irreversible P2Y12 platelet inhibitors clopidogrel and prasugrel led to a 1-hour decrease in IPA followed by an increase in inhibition of platelet aggregation beginning at about one hour. This time course of platelet inhibition reflects the pharmacokinetics of Cangrelor (offset) followed by the absorption and metabolism of clopidogrel and prasugrel to active metabolites (onset). Administration of ticagrelor, a reversible P2Y12 platelet inhibitor, during the Cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hours following discontinuation of the Cangrelor infusion. Administering ticagrelor during Cangrelor infusion does not attenuate the anti-platelet effect of ticagrelor.
In vitro studies suggest that neither Cangrelor nor its major metabolites inhibit the activity of the hepatic CYP isoenzymes at therapeutic concentrations. Therefore, Cangrelor administration is not expected to interfere with the hepatic metabolism of other concomitantly administered therapeutic agents.
Nonclinical Toxicology
No carcinogenicity studies were conducted.
Cangrelor was non-mutagenic and non-clastogenic in genetic toxicology studies, including in vitro bacterial gene mutation assay, mouse lymphoma thymidine kinase assay, chromosome aberration assay in human peripheral lymphocytes, and in vivo bone marrow micronucleus assay in mice.
Impairment of Fertility
Cangrelor had no significant effect on male or female rats fertility treated for 28 days, or on early embryonic development at steady state plasma concentration (Css) of approximately the same as that achieved in the PCI setting at the MRHD.
Clinical Studies
CHAMPION PHOENIX Trial
The CHAMPION PHOENIX trial was intended to test whether faster platelet inhibition with Cangrelor at the time of PCI would reduce the rate of periprocedural thrombotic events compared to a drug with a slower antiplatelet effect, clopidogrel, given at about the time of PCI. It was a randomized, double-blind study in which patients with coronary artery disease (stable angina, UA/NSTEMI, STEMI) requiring PCI and receiving standard therapy including aspirin and heparin or bivalirudin were randomized 1:1 to Cangrelor (n=5472) or to clopidogrel 300 or 600 mg (n=5470). Patients who had already taken an oral P2Y12 platelet inhibitor were not eligible to enroll. Patients administered glycoprotein IIb/IIIa inhibitors (GPI) or for whom GPI use was planned were also not eligible to enroll. PHOENIX was thus a study of people undergoing PCI who had not been previously treated with anti-platelet therapy other than aspirin.
The primary outcome measure was the first occurrence of any one of the composite endpoint of all-cause mortality, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) within 48 hours after randomization.
Cangrelor was administered as 30 mcg/kg bolus followed by 4 mcg/kg/min infusion for 2 to 4 hours. Clopidogrel 600 mg was administered immediately at the end of the Cangrelor infusion in patients randomized to Cangrelor. Clopidogrel 300 mg or 600 mg was administered shortly before PCI or shortly afterward, in patients randomized to clopidogrel.
Cangrelor significantly reduced the occurrence of primary composite endpoint events compared to clopidogrel (relative risk reduction [RRR] 22%). Most of the effect was a reduction in post-procedural MIs detected solely by elevations in CK-MB (type 4a MI). Cangrelor did not reduce the risk of death. Table 2 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint.
- Table 2: Primary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population(a))
KENGREAL: Cangrelor's Brand name
A supplementary analysis was also performed omitting two subcomponent events of the primary endpoint that were of lesser clinical significance: intraprocedural stent thrombosis (defined as a new or increasing thrombus within or adjacent to a deployed stent occurring during the index PCI procedure), and myocardial infarction with less than a 10-fold increase in CK-MB, or with less than a 5-fold increase in CK-MB in the presence of new Q waves or new left bundle branch block (LBBB). These results are shown in Table 3.
- Table 3: Supplementary Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT population)
KENGREAL: Cangrelor's Brand name
The effect of Cangrelor appeared to be consistent in a variety of pre-specified and other clinically important subgroups (see Figure 4).
- Figure 4: CHAMPION PHOENIX Study: Primary Efficacy Endpoint by Subgroup (mITT Population(a))
KENGREAL: Cangrelor's Brand name
Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified (patient presentation and weight were not pre-specified subgroups). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
CHAMPION PCI and PLATFORM Trials
Two additional concurrent clinical trials of the effect of Cangrelor in patients undergoing percutaneous coronary intervention, CHAMPION PCI and CHAMPION PLATFORM were conducted and terminated early for futility. They were completed prior to the design and conduct of CHAMPION PHOENIX. The comparative characteristics and outcomes of each trial are shown in Table 4.
- Table 4: Summary of the CHAMPION Trials
How Supplied
Cangrelor is supplied as a sterile lyophilized powder in single-use 10 mL vials.
- NDC # 65293-003-01: 10 mL vial containing 50 mg Cangrelor
- NDC # 65293-003-10: 10 count of 10 mL vials containing 50 mg Cangrelor
Storage
Vials of Cangrelor should be stored at USP Controlled Room Temperature, [20°C to 25°C (68°F to 77°F) with excursions between 15°C and 30°C (59°F and 86°F) permitted].
Images
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Patient Counseling Information
There is limited information regarding Cangrelor Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Cangrelor interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
KENGREAL®
Look-Alike Drug Names
There is limited information regarding Cangrelor Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.