TICAGRELOR Drug Interactions: What You Need to Know

INTERACTIONS

• Avoid use with strong CYP3A inhibitors or CYP3A inducers. ( 7.1 , 7.2 )
• Opioids: Decreased exposure to ticagrelor. Consider use of parenteral anti-platelet agent. ( 7.3 )
• Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. ( 7.4 )
• Rosuvastatin plasma concentrations may increase. Monitor for statin-related adverse effects. ( 7.4 )
• Monitor digoxin levels with initiation of or any change in ticagrelor tablets. ( 7.5 )

7.1 Strong CYP3A Inhibitors Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

7.2 Strong CYP3A Inducers Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.3 Opioids As with other oral P2Y 12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying [ see Clinical Pharmacology ( 12.3 ) ]. Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

7.4 Simvastatin, Lovastatin, Rosuvastatin Ticagrelor tablets increase serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Ticagrelor tablets increase serum concentration of rosuvastatin because rosuvastatin is a BCRP substrate <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.5 Digoxin Ticagrelor tablets inhibit the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in ticagrelor tablets therapy <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

4 CONTRAINDICATIONS

• History of intracranial hemorrhage. ( 4.1 )
• Active pathological bleeding. ( 4.2 )
• Hypersensitivity to ticagrelor or any component of the product. ( 4.3 )

4.1 History of Intracranial Hemorrhage Ticagrelor tablets are contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 ) ,( 14.2 )]</span>.

4.2 Active Bleeding Ticagrelor tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Adverse Reactions (6.1 )]</span>.

4.3 Hypersensitivity Ticagrelor tablets are contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.

AND PRECAUTIONS

• Dyspnea was reported more frequently with ticagrelor tablets than with control agents in clinical trials. Dyspnea from ticagrelor tablets is self-limiting. ( 5.3 )
• Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. ( 5.5 )
• Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). Ticagrelor tablets are not expected to impact PF4 antibody testing for HIT. ( 5.7 )

5.1 Risk of Bleeding Drugs that inhibit platelet function including ticagrelor tablets increase the risk of bleeding <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ]</span> . Patients treated for acute ischemic stroke or TIA Patients at NIHSS &gt; 5 and patients receiving thrombolysis were excluded from THALES and use of ticagrelor tablets in such patients is not recommended.

5.2 Discontinuation of Ticagrelor Tablets in Patients Treated for Coronary Artery Disease Discontinuation of ticagrelor tablets will increase the risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease. If ticagrelor tablets must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart them as soon as possible. When possible, interrupt therapy with ticagrelor tablets for five days prior to surgery that has a major risk of bleeding. Resume ticagrelor tablets as soon as hemostasis is achieved.

5.3 Dyspnea In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with ticagrelor tablets developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients. In a substudy of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment. If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to ticagrelor tablets, no specific treatment is required; continue ticagrelor tablets without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of ticagrelor tablets, consider prescribing another antiplatelet agent.

5.4 Bradyarrhythmias Ticagrelor tablets can cause ventricular pauses <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2 nd or 3 rd degree AV block or bradycardia-related syncope not protected by a pacemaker were excluded from clinical studies and may be at increased risk of developing bradyarrhythmias with ticagrelor.

5.5 Severe Hepatic Impairment Avoid use of ticagrelor tablets in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of ticagrelor tablets patients with severe hepatic impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

5.6 Central Sleep Apnea Central sleep apnea (CSA) including Cheyne-Stokes respiration (CSR) has been reported in the post-marketing setting in patients taking ticagrelor, including recurrence or worsening of CSA/CSR following rechallenge. If central sleep apnea is suspected, consider further clinical assessment.

5.7 Laboratory Test Interferences False negative functional tests for Heparin Induced Thrombocytopenia (HIT) Ticagrelor tablets have been reported to cause false negative results in platelet functional tests (including the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y 12 -receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s serum/plasma. Information on concomitant treatment with ticagrelor tablets is required for interpretation of HIT functional tests. Based on the mechanism of ticagrelor tablets interference, ticagrelor tablets are not expected to impact PF4 antibody testing for HIT.