Ticagrelor

Chemical formula: C₂₃H₂₈F₂N₆O₄S  Molecular mass: 522.568 g/mol  PubChem compound: 9871419

Interactions

Ticagrelor interacts in the following cases:

CYP3A inducers

Co-administration of rifampicin with ticagrelor decreased ticagrelor Cmax and AUC by 73% and 86%, respectively. The Cmax of the active metabolite was unchanged and the AUC was decreased by 46%, respectively. Other CYP3A inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to ticagrelor as well. Co-administration of ticagrelor with potent CYP3A inducers may decrease exposure and efficacy of ticagrelor, therefore, their concomitant use with ticagrelor is discouraged.

CYP3A4 substrates

Ticagrelor is a mild CYP3A4 inhibitor. Co-administration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (i.e. cisapride or ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products.

Grapefruit

A 2-fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 × 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients.

Potent P-gp inhibitors and moderate CYP3A4 inhibitors

No data are available on concomitant use of ticagrelor with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution.

Strong CYP3A4 inhibitors

Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor.

Co-administration of ketoconazole with ticagrelor increased the ticagrelor Cmax and AUC equal to 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active metabolite were reduced by 89% and 56%, respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir and atazanavir) would be expected to have similar effects and therefore concomitant use of strong CYP3A4 inhibitors with ticagrelor is contraindicated.

Moderate CYP3A4 inhibitors

Co-administration of diltiazem with ticagrelor increased the ticagrelor Cmax by 69% and AUC to 2.7-fold and decreased the active metabolite Cmax by 38% and AUC was unchanged. There was no effect of ticagrelor on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin and fluconazole) would be expected to have a similar effect and can as well be co-administered with ticagrelor.

Moderate hepatic impairment

Only limited information is available in patients with moderate hepatic impairment. Dose adjustment is not recommended, but ticagrelor should be used with caution.

Heparin, enoxaparin, desmopressin

Co-administration of ticagrelor with heparin, enoxaparin or desmopressin had no effect on activated partial thromboplastin time (aPTT), activated coagulation time (ACT) or factor Xa assays. However, due to potential pharmacodynamic interactions, caution should be exercised with the concomitant administration of ticagrelor with medicinal products known to alter haemostasis.

Beta blockers, diltiazem, verapamil, digoxin

Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed in the PLATO trial after concomitant administration with one or more medicinal products known to induce bradycardia (e.g. 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).

Selective serotonin reuptake inhibitors (SSRIs)

Due to reports of cutaneous bleeding abnormalities with SSRIs (e.g. paroxetine, sertraline and citalopram), caution is advised when administering SSRIs with ticagrelor as this may increase the risk of bleeding.

Atorvastatin

Co-administration of atorvastatin and ticagrelor increased atorvastatin acid Cmax by 23% and AUC by 36%. Similar increases in AUC and Cmax were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.

Ciclosporin

Co-administration of cyclosporine (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of cyclosporine. There was no effect of ticagrelor on cyclosporine blood levels.

Digoxin

Concomitant administration of ticagrelor increased the digoxin Cmax by 75% and AUC by 28%. The mean trough digoxin levels were increased about 30% with ticagrelor co-administration with some individual maximum increases to 2-fold. In the presence of digoxin, the Cmax and AUC of ticagrelor and its active metabolite were not affected. Therefore, appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent medicinal products like digoxin concomitantly with ticagrelor.

Levonorgestrel, ethinylestradiol

Co-administration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with ticagrelor.

Morphine

A delayed and decreased exposure to oral P2Y12 inhibitors, including ticagrelor and its active metabolite, has been observed in patients with ACS treated with morphine (35% reduction in ticagrelor exposure). This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced ticagrelor efficacy in patients co-administered ticagrelor and morphine. In patients with ACS, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Simvastatin, lovastatin

Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by 81% and AUC by 56% and increased simvastatin acid Cmax by 64% and AUC by 52% with some individual increases equal to 2- to 3-fold. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause adverse reactions of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. Ticagrelor may have similar effect on lovastatin. The concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended.

Creatinine elevations

Creatinine levels may increase during treatment with ticagrelor. The mechanism has not been elucidated. Renal function should be checked according to routine medical practice. In patients with ACS, it is recommended that renal function is also checked one month after initiating the treatment with ticagrelor, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB).

Dyspnoea, asthma, chronic obstructive pulmonary disease (COPD)

Dyspnoea was reported in patients treated with ticagrelor. Dyspnoea is usually mild to moderate in intensity and often resolves without need for treatment discontinuation. Patients with asthma/chronic obstructive pulmonary disease (COPD) may have an increased absolute risk of experiencing dyspnoea with ticagrelor. Ticagrelor should be used with caution in patients with history of asthma and/or COPD. The mechanism has not been elucidated. If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with ticagrelor should be stopped.

Surgery

Patients should be advised to inform physicians and dentists that they are taking ticagrelor before any surgery is scheduled and before any new medicinal product is taken.

In PLATO patients undergoing coronary artery bypass grafting (CABG), ticagrelor had more bleeding than clopidogrel when stopped within 1 day prior to surgery but a similar rate of major bleeds compared to clopidogrel after stopping therapy 2 or more days before surgery. If a patient is to undergo elective surgery and antiplatelet effect is not desired, ticagrelor should be discontinued 5 days prior to surgery.

Uric acid increase

Hyperuricaemia may occur during treatment with ticagrelor. Caution is advised in patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged.

Pregnancy

There are no or limited amount of data from the use of ticagrelor in pregnant women. Studies in animals have shown reproductive toxicity. Ticagrelor is not recommended during pregnancy.

Nursing mothers

Available pharmacodynamic/toxicological data in animals have shown excretion of ticagrelor and its active metabolites in milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ticagrelor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential

Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ticagrelor therapy.

Fertility

Ticagrelor had no effect on male or female fertility in animals.

Effects on ability to drive and use machines

Ticagrelor has no or negligible influence on the ability to drive and use machines. During treatment with ticagrelor, dizziness and confusion have been reported. Therefore, patients who experience these symptoms should be cautious while driving or using machines.

Adverse reactions


Summary of the safety profile

The safety profile of ticagrelor has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients.

In PLATO, patients on ticagrelor had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%). In PEGASUS, patients on ticagrelor had a higher incidence of discontinuation due to adverse events compared to ASA therapy alone (16.1% for ticagrelor 60 mg with ASA vs. 8.5% for ASA therapy alone). The most commonly reported adverse reactions in patients treated with ticagrelor were bleeding and dyspnoea.

List of adverse reactions

The following adverse reactions have been identified following studies or have been reported in post-marketing experience with ticagrelor.

Adverse reactions are listed by MedDRA System Organ Class (SOC). Within each SOC the adverse reactions are ranked by frequency category. Frequency categories are defined according to the following conventions: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon: Tumour bleedingsa

Blood and lymphatic system disorders

Very common: Blood disorder bleedingsb

Immune system disorders

Uncommon: Hypersensitivity including angioedemac

Metabolism and nutrition disorders

Very common: Hyperuricaemiad

Common: Gout/Gouty Arthritis

Psychiatric disorders

Uncommon: Confusion

Nervous system disorders

Common: Dizziness, Syncope, Headache

Uncommon: Intracranial haemorrhage

Eye disorders

Uncommon: Eye haemorrhagee

Ear and labyrinth disorders

Common: Vertigo

Uncommon: Ear haemorrhage

Vascular disorders

Common: Hypotension

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnoea

Common: Respiratory system bleedingsf

Gastrointestinal disorders

Common: Gastrointestinal haemorrhageg, Diarrhoea, Nausea, Dyspepsia, Constipation

Uncommon: Retroperitoneal haemorrhage

Skin and subcutaneous tissue disorders

Common: Subcutaneous or dermal bleedingh, Rash, Pruritus

Musculoskeletal connective tissue and bone

Uncommon: Muscular bleedingsi

Renal and urinary disorders

Common: Urinary tract bleedingj

Reproductive system and breast disorders

Uncommon: Reproductive system bleedingsk

Investigations

Common: Blood creatinine increasedd

Injury, poisoning and procedural complications

Common: Post procedural haemorrhage, Traumatic bleedingsl

a e.g. bleeding from bladder cancer, gastric cancer, colon cancer
b e.g. increased tendency to bruise, spontaneous haematoma, haemorrhagic diathesis
c Identified in post-marketing experience
d Frequencies derived from lab observations (Uric acid increases to >upper limit of normal from baseline below or within reference range. Creatinine increases of >50% from baseline.) and not crude adverse event report frequency.
e e.g. conjunctival, retinal, intraocular bleeding
f e.g. epistaxis, haemoptysis
g e.g. gingival bleeding, rectal haemorrhage, gastric ulcer haemorrhage
h e.g. ecchymosis, skin haemorrhage, petechiae
i e.g. haemarthrosis, muscle haemorrhage
j e.g. haematuria, cystitis haemorrhagic
k e.g. vaginal haemorrhage, haematospermia, postmenopausal haemorrhage
l e.g. contusion, traumatic haematoma, traumatic haemorrhage

Description of selected adverse reactions

Bleeding

Bleeding findings in PLATO

Overall outcome of bleeding rates in the PLATO study are shown in the following table.

Analysis of overall bleeding events, Kaplan-Meier estimates at 12 months (PLATO):

 Ticagrelor 90 mg twice daily N=9235Clopidogrel N=9186p-value*
PLATO Total Major11.611.20.4336
PLATO Major Fatal/Life-Threatening5.85.80.6988
Non-CABG PLATO Major4.53.80.0264
Non-Procedural PLATO Major3.12.30.0058
PLATO Total Major + Minor16.114.60.0084
Non-Procedural PLATO Major + Minor5.94.3<0.0001
TIMI-defined Major7.97.70.5669
TIMI-defined Major + Minor11.410.90.3272

Bleeding category definitions:

Major Fatal/Life-threatening Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused; or fatal; or intracranial; or intrapericardial with cardiac tamponade; or with hypovolaemic shock or severe hypotension requiring pressors or surgery.
Major Other: Clinically apparent with 30-50 g/L decrease in haemoglobin or 2-3 red cell units transfused; or significantly disabling.
Minor Bleed: Requires medical intervention to stop or treat bleeding.
TIMI Major Bleed: Clinically apparent with >50 g/L decrease in haemoglobin or intracranial haemorrhage.
TIMI Minor Bleed: Clinically apparent with 30-50 g/L decrease in haemoglobin.
* p-value calculated from Cox proportional hazards model with treatment group as the only explanatory variable.

Ticagrelor and clopidogrel did not differ in rates of PLATO Major Fatal/Life-threatening bleeding, PLATO total Major bleeding, TIMI Major bleeding, or TIMI Minor bleeding. However, more PLATO combined Major + Minor bleeding occurred with ticagrelor compared with clopidogrel. Few patients in PLATO had fatal bleeds: 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel.

Age, sex, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history, including a previous stroke or transient ischaemic attack, all did not predict either overall or non-procedural PLATO Major bleeding. Thus, no particular group was identified at risk for any subset of bleeding.

CABG-related bleeding:

In PLATO, 42% of the 1584 patients (12% of cohort) who underwent coronary artery bypass graft (CABG) surgery had a PLATO Major Fatal/Life-threatening bleeding with no difference between treatment groups. Fatal CABG bleeding occurred in 6 patients in each treatment group.

Non-CABG related bleeding and non-procedural related bleeding:

Ticagrelor and clopidogrel did not differ in non-CABG PLATO-defined Major Fatal/Life-threatening bleeding, but PLATO-defined Total Major, TIMI Major, and TIMI Major + Minor bleeding were more common with ticagrelor. Similarly, when removing all procedure related bleeds, more bleeding occurred with ticagrelor than with clopidogrel. Discontinuation of treatment due to non-procedural bleeding was more common for ticagrelor (2.9%) than for clopidogrel (1.2%; p<0.001).

Intracranial bleeding:

There were more intracranial non-procedural bleeds with ticagrelor (n=27 bleeds in 26 patients, 0.3%) than with clopidogrel (n=14 bleeds, 0.2%), of which 11 bleeds with ticagrelor and 1 with clopidogrel were fatal. There was no difference in overall fatal bleeds.

Bleeding findings in PEGASUS

Overall outcome of bleeding events in the PEGASUS study are shown in the folowing table.

Analysis of overall bleeding events, Kaplan-Meier estimates at 36 months (PEGASUS):

 Ticagrelor 60 mg twice daily + ASA N=6958ASA alone N=6996 
Safety EndpointsKM%Hazard Ratio (95% CI) KM%p-value
TIMI-defined bleeding categories
TIMI Major2.32.32 (1.68, 3.21) 1.1<0.0001
Fatal0.31.00 (0.44, 2.27) 0.31.0000
ICH0.61.33 (0.77, 2.31) 0.50.3130
Other TIMI Major1.63.61 (2.31, 5.65) 0.5<0.0001
TIMI Major or Minor3.42.54 (1.93, 3.35) 1.4<0.0001
TIMI Major or Minor or Requiring medical attention16.62.64 (2.35, 2.97) 7.0<0.0001
PLATO-defined bleeding categories
PLATO Major3.52.57 (1.95, 3.37) 1.4<0.0001
Fatal/Life-threatening2.42.38 (1.73, 3.26) 1.1<0.0001
Other PLATO Major1.13.37 (1.95, 5.83) 0.3<0.0001
PLATO Major or Minor15.22.71 (2.40, 3.08) 6.2<0.0001

Bleeding category definitions:

TIMI Major: Fatal bleeding, OR any intracranial bleeding, OR clinically overt signs of haemorrhage associated with a drop in haemoglobin (Hgb) of ≥50 g/L, or when Hgb is not available, a fall in haematocrit (Hct) of 15%.
Fatal: A bleeding event that directly led to death within 7 days.
ICH: Intracranial haemorrhage.
Other TIMI Major: Non-fatal non-ICH TIMI Major bleeding.
TIMI Minor: Clinically apparent with 30-50 g/L decrease in haemoglobin.
TIMI Requiring medical attention: Requiring intervention, OR leading to hospitalisation, OR prompting evaluation.
PLATO Major Fatal/life-threatening: Fatal bleeding, OR any intracranial bleeding, OR intrapericardial with cardiac tamponade, OR with hypovolaemic shock or severe hypotension requiring pressors/inotropes or surgery OR clinically apparent with >50 g/L decrease in haemoglobin or ≥4 red cell units transfused.
PLATO Major Other: Significantly disabling, OR clinically apparent with 30-50 g/L decrease in haemoglobin, OR 2-3 red cell units transfused.
PLATO Minor: Requires medical intervention to stop or treat bleeding.

In PEGASUS, TIMI Major bleeding for ticagrelor 60 mg twice daily was higher than for ASA alone. No increased bleeding risk was seen for fatal bleeding and only a minor increase was observed in intracranial haemorrhages, as compared to ASA therapy alone. There were few fatal bleeding events in the study, 11 (0.3%) for ticagrelor 60 mg and 12 (0.3%) for ASA therapy alone. The observed increased risk of TIMI Major bleeding with ticagrelor 60 mg was primarily due to a higher frequency of Other TIMI Major bleedings driven by events in the gastrointestinal SOC.

Increased bleeding patterns similar to TIMI Major were seen for TIMI Major or Minor and PLATO Major and PLATO Major or Minor bleeding categories. Discontinuation of treatment due to bleeding was more common with ticagrelor 60 mg compared to ASA therapy alone (6.2% and 1.5%, respectively). The majority of these bleedings were of less severity (classified as TIMI Requiring medical attention), e.g. epistaxis, bruising and haematomas.

The bleeding profile of ticagrelor 60 mg was consistent across multiple pre-defined subgroups (e.g. by age, gender, weight, race, geographic region, concurrent conditions, concomitant therapy and medical history) for TIMI Major, TIMI Major or Minor and PLATO Major bleeding events.

Intracranial bleeding:

Spontaneous ICHs were reported in similar rates for ticagrelor 60 mg and ASA therapy alone (n=13, 0.2% in both treatment groups). Traumatic and procedural ICHs showed a minor increase with ticagrelor 60 mg treatment, (n=15, 0.2%) compared with ASA therapy alone (n=10, 0.1%). There were 6 fatal ICHs with ticagrelor 60 mg and 5 fatal ICHs with ASA therapy alone. The incidence of intracranial bleeding was low in both treatment groups given the significant comorbidity and CV risk factors of the population under study.

Dyspnoea

Dyspnoea, a sensation of breathlessness, is reported by patients treated with ticagrelor. In PLATO, dyspnoea adverse events (AEs) (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea), when combined, was reported by 13.8% of patients treated with ticagrelor and by 7.8% of patients treated with clopidogrel. In 2.2% of patients taking ticagrelor and by 0.6% taking clopidogrel investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel),. Most reported symptoms of dyspnoea were mild to moderate in intensity, and most were reported as a single episode early after starting treatment.

Compared with clopidogrel, patients with asthma/COPD treated with ticagrelor may have an increased risk of experiencing non-serious dyspnoea (3.29% ticagrelor versus 0.53% clopidogrel) and serious dyspnoea (0.38% ticagrelor versus 0.00% clopidogrel). In absolute terms, this risk was higher than in the overall PLATO population. Ticagrelor should be used with caution in patients with history of asthma and/or COPD.

About 30% of episodes resolved within 7 days. PLATO included patients with baseline congestive heart failure, COPD or asthma; these patients, and the elderly, were more likely to report dyspnoea. For ticagrelor, 0.9% of patients discontinued study drug because of dyspnoea compared with 0.1% taking clopidogrel. The higher incidence of dyspnoea with ticagrelor is not associated with new or worsening heart or lung disease. Ticagrelor does not affect tests of pulmonary function.

In PEGASUS, dyspnoea was reported in 14.2% of patients taking ticagrelor 60 mg twice daily and in 5.5% of patients taking ASA alone. As in PLATO, most reported dyspnoea was mild to moderate in intensity. Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, COPD or asthma at baseline.

Investigations

Uric acid elevations: In PLATO, serum uric acid increased to more than upper limit of normal in 22% of patients receiving ticagrelor compared to 13% of patients receiving clopidogrel. The corresponding numbers in PEGASUS were 9.1%, 8.8% and 5.5% for ticagrelor 90 mg, 60 mg and placebo, respectively. Mean serum uric acid increased approximately 15% with ticagrelor compared to approximately 7.5% with clopidogrel and after treatment was stopped, decreased to approximately 7% on ticagrelor but with no decrease observed for clopidogrel. In PEGASUS, a reversible increase in mean serum uric acid levels of 6.3% and 5.6% was found for ticagrelor 90 mg and 60 mg, respectively, compared to a 1.5% decrease in the placebo group. In PLATO, the frequency of gouty arthritis was 0.2% for ticagrelor vs. 0.1% for clopidogrel. The corresponding numbers for gout/gouty arthritis in PEGASUS were 1.6%, 1.5% and 1.1% for ticagrelor 90 mg, 60 mg and placebo, respectively.

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