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Suzetrigene

2026-05-04T21:21:39Z

Anum Ijaz:

{{DrugProjectFormSinglePage
|authorTag={{AIJ}}
|genericName=JOURNAVX
|aOrAn=a
|drugClass=sodium channel blocker
|indicationType=treatment
|indication=of moderate to severe pain acute pain, including postoperative pain, in adults.
|adverseReactions=pruritus, muscle spasms, increased creatine phosphokinase, and rash.

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|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' There is limited information regarding Black Box Warning of Suzetrigene in adult patients.
|fdaLIADAdult=Adult Indications.
JOURNAVX is indicated for the treatment of moderate to severe acute pain, including postoperative pain, in adults. Use JOURNAVX for the shortest duration, consistent with individual patient treatment goals. Use of JOURNAVX for the treatment of moderate to severe acute pain has not been studied beyond 14 days.

Recommended Dosage and Administration:
* The recommended starting dose of JOURNAVX is 100 mg orally.
* Take the starting dose on an empty stomach at least 1 hour before or 2 hours after food to avoid delay in onset of action.
* Clear liquids may be consumed during this time (e.g., water, apple juice, vegetable broth, tea, black coffee).
* Starting 12 hours after the initial dose, take 50 mg of JOURNAVX orally every 12 hours.
* Avoid food or drink containing grapefruit during treatment with JOURNAVX.

Dosage Form.
* Tablets: 50 mg, blue, film-coated, oblong tablets debossed with "VX50" on one side and plain on the other.

Recommedations regarding Missed Doses.
For patients on the standard recommended dosing schedule:
* If a dose is missed, take the missed dose as soon as possible and then take the next scheduled dose at the recommended time.
* If two or more doses are missed, take 100 mg and then take the next scheduled dose at the recommended time.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Suzetrigene in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Suzetrigene in adult patients.
|fdaLIADPed=There is limited information regarding indications and dosage of Suzetrigene in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Suzetrigene in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Suzetrigene in pediatric patients.
|contraindications=* JOURNAVX is contraindicated in patients taking strong CYP3A inhibitors.
* When JOURNAVX is administered to patients taking moderate CYP3A inhibitors reduce the JOURNAVX dose, as described below:

Dose 1: The recommended starting dose of JOURNAVX is 100 mg orally. Take the starting dose on an empty stomach at least 1 hour before or 2 hours after food. Clear liquids may be consumed during this time (e.g., water, apple juice, vegetable broth, tea, black coffee).

Doses 2, 3, and 4: Starting 12 hours after the initial dose, take 50 mg of JOURNAVX orally every 12 hours. Take these doses with or without food.

Dose 5 and Subsequent Doses: Starting 12 hours after Dose 4, take 50 mg of JOURNAVX orally every 24 hours. Take these dose(s) with or without food.

Avoid food or drink containing grapefruit during treatment with JOURNAVX.
|warnings=FDA reported warnings and precautions associated with the JOURNAVX are as follows:

'''Increased Risk of Adverse Reactions with Concomitant Use with Strong or Moderate CYP3A Inhibitors'''
Strong and moderate CYP3A inhibitors increase suzetrigine and M6-SUZ (active metabolite) exposures which may cause JOURNAVX adverse reactions. Concomitant use of JOURNAVX with strong CYP3A inhibitors is contraindicated. Reduce the JOURNAVX dosage with moderate CYP3A inhibitors.

'''Risk of Drug Interactions with Certain CYP3A Substrates'''
Suzetrigine is an inducer of CYP3A. If JOURNAVX is used concomitantly with sensitive CYP3A substrates or CYP3A substrates where minimal concentration changes may lead to loss of efficacy, refer to the Prescribing Information for the CYP3A substrates for dosing instructions. Dosage adjustment of the concomitant CYP3A substrates may be required when initiating or discontinuing JOURNAVX.

'''Risk of Drug Interactions with Certain Hormonal Contraceptives'''
JOURNAVX-treated patients taking concomitant hormonal contraceptives containing progestins other than levonorgestrel and norethindrone should use additional nonhormonal contraceptives (such as condoms) or use alternative contraceptives (e.g., a combined oral contraceptive containing ethinyl estradiol as the estrogen and levonorgestrel or norethindrone as the progestin, an intrauterine system) during JOURNAVX treatment and for 28 days after discontinuation of JOURNAVX.

'''Risk of Adverse Reactions in Patients with Moderate and Severe Hepatic Impairment'''
Patients with moderate hepatic impairment have higher systemic exposures of suzetrigine and M6-SUZ (active metabolite) than those with normal hepatic function which may increase the risk of JOURNAVX related adverse reactions.Avoid use of JOURNAVX in patients with severe hepatic impairment (Child-Pugh Class C). The recommended JOURNAVX dosage is lower in patients with moderate hepatic impairment (Child-Pugh Class B) than those with normal hepatic function.
|clinicalTrials=The safety profile of JOURNAVX is primarily based on data from the pooled, double-blind, placebo- and active-controlled trials in 874 adult patients with moderate to severe acute pain following full abdominoplasty (Trial 1) and bunionectomy (Trial 2), with supportive safety data from one single arm trial in 256 adult patients with moderate to severe acute pain in a broad range of acute pain conditions (Trial 3).

'''Nausea and Vomiting'''

In Trial 1, the incidence of patients who experienced either nausea or vomiting was 20% in JOURNAVX-treated patients, 33% in HB/APAP-treated patients, and 25% in placebo-treated patients. In Trial 2, the incidence of patients who experienced either nausea or vomiting was 9% in JOURNAVX-treated patients, 16% in HB/APAP-treated patients, and 12% in placebo-treated patients.

'''Laboratory Abnormalities'''

Creatine Phosphokinase Elevations: In Trials 1 and 2, 2.9% of JOURNAVX-treated patients and 1.2% of placebo-treated patients had a creatine phosphokinase (CPK) level > 3 times the upper limit of normal. The incidence of increased blood CPK was 1.1% in JOURNAVX-treated patients and 0.5% in placebo-treated patients. All reports of CPK elevations occurred in the post-surgical setting. There were no associated signs or symptoms, no serious adverse reactions, and no patients required treatment discontinuation or interruption.

Decreased Estimated Glomerular Filtration Rate: In Trials 1 and 2, 2.5% of JOURNAVX-treated patients and 0.9% of placebo-treated patients had a decrease in estimated glomerular filtration rate (eGFR) of ≥ 25% but < 50%. Follow-up eGFR data for these controlled trials was not available after treatment discontinuation. Similar decreases in eGFR also occurred in Trial 3 (the open-label Phase 3 study) and appeared to resolve to baseline by the final safety follow-up visit. There was no control arm for comparison. There were no adverse reactions of eGFR decrease in JOURNAVX-treated patients.

'''Adverse Reactions from the Open-Label Study (Trial 3)'''

* In an open-label study of patients with moderate to severe acute pain following a surgical procedure or nonsurgical condition [NCT05661734], a total of 256 adult patients received at least one dose of JOURNAVX. Patients received 100 mg as a first dose, then 50 mg every 12 hours and continued to receive JOURNAVX for up to 14 days or until their pain resolved. Rescue medication of 650 mg of acetaminophen and 400 mg of ibuprofen together every 6 hours was permitted as needed for pain relief. The patients' perceptions of pain control was captured by patient global assessment (PGA). The mean duration of treatment with JOURNAVX was 9.6 days. The majority of patients were female (68%), and the median age was 43 years (range: 18 to 78).

* In Trial 3, a total of 222 (87%) patients received JOURNAVX for post-surgical pain; orthopedic surgery was the most common (e.g., ligament operation, arthrodesis), followed by plastic surgery (e.g., liposuction, mammoplasty), otorhinolaryngologic surgery (e.g., nasal septal operation, turbinoplasty), and general and urologic surgery (e.g., inguinal hernia repair). Thirty-four (13%) patients received JOURNAVX for non-surgical pain (e.g., arthralgias, limb pain, and sprains/strains).

* The proportion of patients who discontinued study drug prematurely was 2% due to adverse events (arrhythmia [0.4%], nausea [0.4%], somnolence [0.4%], rash [0.4%]) and 1.6% due to lack of efficacy.

* The safety profile of JOURNAVX in Trial 3 was consistent with that observed in Trials 1 and 2.
|drugInteractions=====Effect of Other Drugs on JOURNAVX====
* Food or drink containing grapefruit should be avoided during treatment with JOURNAVX.

Table 3.

====Effect of JOURNAVX on Other Drugs====

'''CYP3A Substrates'''

* If JOURNAVX is used concomitantly with sensitive CYP3A substrates or CYP3A substrates where minimal concentration changes may lead to loss of efficacy, refer to the Prescribing Information for the CYP3A substrates for dosing instructions. Dosage modification of the concomitant CYP3A substrates may be required when initiating or discontinuing JOURNAVX.

'''Hormonal Contraceptives'''

* JOURNAVX-treated patients using hormonal contraceptives containing progestins other than levonorgestrel and norethindrone should use additional nonhormonal contraceptives (such as condoms), or use alternative contraceptives (such as a combined oral contraceptive containing ethinyl estradiol as the estrogen and levonorgestrel or norethindrone as the progestin, or an intrauterine system) during treatment with JOURNAVX and for 28 days after discontinuation of JOURNAVX.
* JOURNAVX did not result in clinically significant changes in the pharmacokinetics of ethinyl estradiol and levonorgestrel when used concomitantly with an oral contraceptive containing ethinyl estradiol and levonorgestrel.
|useInPregnancyFDA='''Risk Summary'''

* There are no available data on the use of JOURNAVX during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.
* In animal reproduction studies in rats, effects on implantation and maintenance of pregnancy occurred at oral suzetrigine doses of ≥ 2.2-times the maximum recommended human dose (MRHD) when administered during early embryonic development or throughout organogenesis.
* In a pre- and postnatal development study, reduced mean gestation length and increased postnatal pup mortality were observed at maternal rat exposures of 1.6-times the MRHD and decreased rat pup body weights were observed during the period of birth to weaning at maternal exposures of 2.2-times the MRHD.
* No malformations were observed when suzetrigine was administered orally to rats and rabbits during the period of organogenesis at doses up to 2.2- and 5.9-times, respectively, the MRHD. The clinical relevance of these findings is unclear.
* The background risk of major birth defects and miscarriage in patients with moderate to severe acute pain 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% to 4% and 15% to 20%, respectively.
|useInNursing='''Risk Summary'''

* There are no data on the presence of suzetrigine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.
* Suzetrigine is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
* The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for JOURNAVX and any potential adverse effects on the breastfed child from JOURNAVX or from the underlying maternal condition.
|useInPed=The safety and effectiveness of JOURNAVX has not been established in pediatric patients.
|useInGeri=* Of the total 1130 patients with moderate to severe acute pain who received JOURNAVX in the Phase 3 studies, 71 patients (6.3%) were 65 years of age and older.
* Clinical studies of JOURNAVX did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, based on population pharmacokinetic analyses in patients with ages ranging from 18 to 75 years, age does not have a clinically relevant impact on suzetrigine exposure.
|useInRenalImpair=* JOURNAVX has not been studied in patients with renal impairment of eGFR < 15 mL/min.
* Avoid use of JOURNAVX in patients with renal impairment of eGFR < 15 mL/min.
* The recommended dosage in patients with eGFR > 15 mL/min is the same as those with normal kidney function.
|useInHepaticImpair=* Avoid use of JOURNAVX in patients with severe hepatic impairment (Child-Pugh Class C.
* The recommended JOURNAVX dosage is lower in patients with moderate hepatic impairment (Child-Pugh Class B) than those with normal hepatic function.
* The recommended dosage in patients with mild hepatic impairment (Child-Pugh Class A) is the same as those with normal hepatic function.
* Patients with moderate hepatic impairment had greater suzetrigine and M6-SUZ (the active metabolite) exposure than those with normal hepatic function, which may increase the risk of suzetrigine adverse reactions.

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|useInReproPotential='''Contraception'''

* Advise patients using hormonal contraceptives containing progestins other than levonorgestrel and norethindrone to use an additional nonhormonal contraceptive or to use alternative contraceptives during JOURNAVX treatment and for 28 days after discontinuation of JOURNAVX.

'''Infertility'''
* In a female fertility study in rats, increased pre-implantation loss was observed at oral suzetrigine doses of ≥ 2.2-times the MRHD when administered prior to mating and through Gestation Day 7.
* Following discontinuation of suzetrigine for 4 weeks, the increased pre-implantation loss in rats was not observed.
* The finding in rats may be explained by the effect of suzetrigine on the rat progesterone receptor, which was more sensitive to suzetrigine than the human progesterone receptor based on in vitro studies.
* JOURNAVX may reversibly impact the likelihood of females of reproductive potential to become pregnant while on treatment. Patients using contraceptives should continue to use contraceptives.
|overdose=* No specific antidote is available for overdose with JOURNAVX. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
|mechAction=Suzetrigine is a selective blocker of the NaV1.8 voltage-gated sodium channel, compared to other known voltage-gated sodium channels (NaV1.1 through 1.9). NaV1.8 is expressed in peripheral sensory neurons including dorsal root ganglion neurons, where its role is to transmit pain signals (action potentials). By selectively inhibiting NaV1.8 channels, suzetrigine inhibits transmission of pain signals to the spinal cord and brain. M6-SUZ, a major active metabolite, is a less potent inhibitor of NaV1.8 than suzetrigine by 3.7-fold.
|structure=The active ingredient in JOURNAVX (suzetrigine) tablets is suzetrigine, a sodium channel blocker, which has the following chemical name:

4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-amido]pyridine-2-carboxamide. Its molecular formula is C21H20F5N3O4.

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|PD='''Cardiac Electrophysiology'''

At 2 times the exposure of the maximum recommended JOURNAVX dose, clinically significant QTc prolongation was not observed.
|nonClinToxic='''Carcinogenesis'''

* Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.

'''Mutagenesis'''

* Suzetrigine was not mutagenic in the bacterial reverse mutation assay (Ames test), or clastogenic in the in vitro micronucleus assay with a human TK6 lymphoblastoid cell line, or in the in vivo rat bone marrow micronucleus assay.

'''Impairment of Fertility'''

* In a female fertility study, female rats were treated orally with suzetrigine at 5, 10, and 15 mg/kg/day for a minimum of 14 days prior to mating, throughout mating, and through Gestation Day 7. These doses are approximately 0.57, 1.6, and 2.2-times the steady state MRHD exposure based on AUC. Increased pre-implantation loss was observed at 15 mg/kg (approximately 2.2-times the MRHD based on AUC).
* In a male fertility study, male rats were treated orally with suzetrigine at 200, 600, and 1000 mg/kg/day for a minimum of 28 days prior to mating and through mating. These doses are 3.6, 9.7, and 13.8-times the steady state MRHD exposure based on AUC, respectively. Suzetrigine had no effects on sperm parameters (motility, concentration, or morphology), reproductive performance or uterine parameters (number of implants, viable implants, pre-implantation loss, early resorptions, and post-implantation loss) at any dose.
|clinicalStudies='''Overview of Clinical Studies'''

* The efficacy of JOURNAVX in the treatment of moderate to severe acute pain in adults was established in two randomized, double-blind, placebo and active-controlled trials of acute pain, one following full abdominoplasty (Trial 1) [see Clinical Studies (14.2)] and the other following bunionectomy (Trial 2) [see Clinical Studies (14.3)].
* In each trial, pain intensity was measured using a patient-reported 11-point numeric pain rating scale (NPRS), ranging from 0 to 10, where zero corresponds to no pain and 10 corresponds to the worst pain imaginable.
* Patients were eligible for study participation if they had moderate to severe pain on the verbal categorical rating system (VRS) and a pain score of ≥ 4 on the NPRS, within 4 hours of the abdominoplasty completion (Trial 1) or during the 9-hour period after discontinuation of regional anesthesia following bunionectomy (Trial 2).
* Once eligible, patients were randomized to receive oral JOURNAVX, placebo, or hydrocodone bitartrate/acetaminophen (HB/APAP) for a duration of 48 hours.
* For the JOURNAVX treatment regimen, patients received an initial loading dose of 100 mg JOURNAVX, followed by 50 mg every 12 hours.
* For the HB/APAP-control regimen, patients received 5 mg/325 mg every 6 hours. * For both studies, 400 mg of ibuprofen every 6 hours, as needed for pain relief, was permitted as a rescue medication.

'''Moderate to Severe Acute Pain Following Full Abdominoplasty'''
* Trial 1 [NCT05558410] evaluated the efficacy of JOURNAVX over 48 hours in 1,118 adult patients with moderate to severe acute pain following a full abdominoplasty procedure (JOURNAVX n = 447, placebo n = 223, and hydrocodone bitartrate/acetaminophen (HB/APAP) n = 448).
* The majority of patients were female (98%), and the mean age was 42 years (range: 18 to 69).
* The study population consisted of 70% White participants, 27% Black or African American participants, 1% Asian participants, 0.8% Native Hawaiian or other Pacific Islander participants, 0.5% American Indian or Alaska Native participants, and 0.9% Other or Multiracial participants, among which 34% identified as Hispanic or Latino. The mean pain score at baseline was 7.4 (range: 4 to 10).
* All baseline characteristics, including NPRS, VRS, and BMI were generally balanced across treatment arms.
* In Trial 1, 89% of patients in the JOURNAVX group completed the treatment period (compared to 75% of patients in the placebo group and 85% of patients in the HB/APAP group), and 9% of patients in the JOURNAVX group discontinued due to lack of efficacy (compared to 22% of patients in the placebo group and 13% of patients in the HB/APAP group).
* Efficacy was evaluated by the time-weighted sum of the pain intensity difference from 0 to 48 hours (SPID48) in the JOURNAVX group compared to the placebo group and then to the HB/APAP group. Treatment with JOURNAVX demonstrated statistically significant superior reduction in pain compared to treatment with placebo.
* The median time to meaningful pain relief (defined as a ≥ 2-point reduction in NPRS) was 119 minutes for patients in the JOURNAVX group and 480 minutes for patients in the placebo group. The median time to onset of perceptible pain relief (defined as a ≥ 1-point reduction in NPRS) for patients in the JOURNAVX group was 34 minutes.

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'''Moderate to Severe Acute Pain Following Bunionectomy'''
* Trial 2 [NCT05553366] evaluated the efficacy of JOURNAVX over 48 hours in 1,073 adult patients with moderate to severe acute pain following bunionectomy (JOURNAVX n = 426, placebo n = 216, and HB/APAP n = 431).
* The majority of patients were female (85%), and the mean age was 48 years (range: 18 to 75).
* The study population consisted of 71% White participants, 24% Black or African American participants, 2% Asian participants, 0.2% Native Hawaiian or other Pacific Islander participants, 1% American Indian or Alaska Native participants, and 1% Other or Multiracial participants, and 0.3% with race missing, among which 34% identified as Hispanic or Latino.
* The mean pain score at baseline was 6.8 (range: 4 to 10). All baseline characteristics, including NPRS, VRS, and BMI were generally balanced across treatment arms.
* In Trial 2, 87% of patients in the JOURNAVX group completed the treatment period (compared to 82% of patients in the placebo group and 90% of patients in the HB/APAP group), and 12% of patients in the JOURNAVX group discontinued due to lack of efficacy (compared to 16% of patients in the placebo group and 8% of patients in the HB/APAP group).
* Efficacy was evaluated by the time-weighted sum of the pain intensity difference from 0 to 48 hours (SPID48) in the JOURNAVX group compared to the placebo group and then to the HB/APAP group.
* In an exploratory analysis, the time-weighted sum of the pain intensity difference from 0 to 24 hours (SPID24) reported using the least square mean was 30.6 in the JOURNAVX group and 19.8 in the placebo group.

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'''Time to Onset of Pain Relief'''

The median time to meaningful pain relief (defined as ≥ 2-point reduction in NPRS) was 240 minutes for patients in the JOURNAVX group and 480 minutes in the placebo group. The median time to onset of perceptible pain relief (defined as a ≥ 1-point reduction in NPRS) for patients in the JOURNAVX group was 60 minutes.
|howSupplied=JOURNAVX (suzetrigine) tablets are supplied as blue, film-coated, oblong tablets containing 50 mg of suzetrigine. Each tablet is debossed with the characters "VX50" on one side and plain on the other, and is packaged as follows:

* 30-count bottle NDC 51167-548-30
* 100-count bottle NDC 51167-548-31
* 100-count Hospital Unit Dose Carton (10 blister cards, each containing 10 tablets) NDC 51167-548-34
|storage=* Store at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C).
|fdaPatientInfo='''Drug Interactions'''

* Ask patients to tell you all the medications they are taking, including any herbal supplements or vitamins.
* Food or drink containing grapefruit should be avoided.
* When used concomitantly with hormonal contraceptives containing a progestin other than levonorgestrel or norethindrone, advise patients to use an additional nonhormonal contraceptive (such as condoms) or use alternative contraceptives during JOURNAVX treatment and for 28 days after discontinuation of JOURNAVX.

'''Females of Reproductive Potential'''
* Advise females of reproductive potential that JOURNAVX may reversibly impact the likelihood to become pregnant while on treatment.
* Patients using contraceptives should continue to use contraceptives.

'''Use in Patients with Hepatic Impairment'''
* Inquire and/or assess whether patients have hepatic impairment.

'''Administration Instructions'''
* Advise patients to take the starting dose of JOURNAVX on an empty stomach at least 1 hour before or 2 hours after food to avoid delay in onset of action.
* Clear liquids may be consumed (such as water, apple juice, vegetable broth, tea, or black coffee) during this time.
* Avoid food or drink containing grapefruit during treatment with JOURNAVX.
* Subsequent doses of JOURNAVX can be taken with or without food.
* Patients should be instructed to swallow JOURNAVX tablets whole (do not chew or crush).
* Inform patients about what to do in the event they miss a dose of JOURNAVX.
|alcohol=Alcohol-Suzetrigene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=JOURNAVX
|lookAlike=There is limited information regarding Look-Alike Drug Names to JOURNAVX.
}}

Hibatullah Abdul Aleem

2026-04-29T16:04:52Z

Hiba Tullah: Created page with "__NOTOC__ ==Hibatullah Abdul Aleem== '''Hibatullah Abdul Aleem''' Contact: Email: [mailto:dr.hibatullah8@gmail.com] ==Current Position== ==Professional Background== ==Education== M.B.B.S fron Shadan Institute Of Medical Sciences ==Brief Biography=="

__NOTOC__
==Hibatullah Abdul Aleem==
'''Hibatullah Abdul Aleem'''
 Contact: 
Email: [mailto:dr.hibatullah8@gmail.com] 

==Current Position==

==Professional Background==

==Education==
M.B.B.S fron Shadan Institute Of Medical Sciences

==Brief Biography==

SANDBOX:HT

2026-04-29T10:02:24Z

Hiba Tullah:

==Thoracic Aortic Aneurysm Surgery==

===Overview===
Indications for surgical repair of a [[thoracic aortic aneurysm]] include rupture; symptoms such as pain consistent with impending rupture; significant [[aortic regurgitation]]; growth of 0.5 cm per year or greater; and attainment of pre-specified absolute size thresholds that vary by aortic segment and underlying aetiology. For asymptomatic patients with degenerative thoracic aneurysm, surgical or endovascular repair is generally indicated when the ascending aorta reaches 5.5 cm or greater, or at smaller diameters in the presence of heritable aortic conditions, rapid growth, or concurrent cardiac surgery. Patients with [[Marfan syndrome]], [[Loeys-Dietz syndrome]], [[bicuspid aortic valve]]-associated aortopathy, or other heritable thoracic aortic disease (HTAD) should be referred to experienced multidisciplinary aortic centres and undergo elective repair at smaller diameters than the general population.<ref name="pmid36322642">{{cite journal |vauthors=Isselbacher EM, Preventza O, Hamilton Black J, Augoustides JG, Beck AW, Bolen MA, Braverman AC, Bray BE, Brown-Zimmerman MM, Chen EP, Collins TJ, DeAnda A, Fanola CL, Girardi LN, Hicks CW, Hui DS, Schuyler Jones W, Kalahasti V, Kim KM, Milewicz DM, Oderich GS, Ogbechie L, Promes SB, Gyang Ross E, Schermerhorn ML, Singleton Times S, Tseng EE, Wang GJ, Woo YJ |title=2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines |journal=Circulation |volume=146 |issue=24 |pages=e334–e482 |date=December 2022 |pmid=36322642 |pmc=9876736 |doi=10.1161/CIR.0000000000001106 |url=}}</ref> A woven [[dacron]] tube graft is most commonly used in the repair of thoracic aortic aneurysms. [[Thoracic endovascular aortic repair]] (TEVAR) is the preferred modality for anatomically suitable descending thoracic aortic aneurysms.

==Surgery==

===Preoperative Medical Optimization===
All patients awaiting elective thoracic aortic surgery should receive aggressive medical therapy directed at reducing aortic wall stress and slowing aneurysm growth.
* '''Blood pressure target''': <130/80 mmHg in all patients with thoracic aortic disease (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>
* '''Beta-blockers''' are first-line antihypertensive therapy in [[Marfan syndrome]] and remain reasonable in other heritable thoracic aortic disease and degenerative aneurysms to reduce dP/dt.<ref name="pmid18579813">{{cite journal |vauthors=Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC |title=Angiotensin II blockade and aortic-root dilation in Marfan's syndrome |journal=N Engl J Med |volume=358 |issue=26 |pages=2787–95 |date=June 2008 |pmid=18579813 |pmc=2692965 |doi=10.1056/NEJMoa0706585 |url=}}</ref>
* '''Angiotensin receptor blockers''' (losartan) showed comparable efficacy to atenolol in pediatric and young adult Marfan patients and may be combined with beta-blockade.<ref name="pmid25405392">{{cite journal |vauthors=Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, Pearson GD, Selamet Tierney ES, Levine JC, Atz AM, Benson DW, Braverman AC, Chen S, De Backer J, Gelb BD, Grossfeld PD, Klein GL, Lai WW, Liou A, Loeys BL, Markham LW, Olson AK, Paridon SM, Pemberton VL, Pierpont ME, Pyeritz RE, Radojewski E, Roman MJ, Sharkey AM, Stylianou MP, Wechsler SB, Young LT, Mahony L |title=Atenolol versus losartan in children and young adults with Marfan's syndrome |journal=N Engl J Med |volume=371 |issue=22 |pages=2061–71 |date=November 2014 |pmid=25405392 |pmc=4386623 |doi=10.1056/NEJMoa1404731 |url=}}</ref>
* '''Statins''' are recommended for cardiovascular risk reduction in patients with atherosclerotic aortic disease (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>
* '''Smoking cessation''' is strongly recommended; ongoing tobacco use is associated with faster aneurysm growth and higher rupture risk.
* '''Avoid fluoroquinolones''' in patients with known aortic aneurysm or heritable aortopathy due to associated risk of dissection and rupture (FDA Drug Safety Communication, 2018).
* '''Strenuous isometric exercise and competitive contact sport''' should be avoided.

===Evaluating the Patient's Risk of Dissection and Rupture===
The annual risk of rupture, dissection, or death is closely related to aneurysm size. The risk increases in a curvilinear fashion and forms the basis for performing surgery when the aorta reaches 5.0 to 5.5 cm in diameter depending on the aortic segment involved and patient-specific risk factors. Cross-sectional area to height ratio and aortic length have emerged as additional predictors of adverse aortic events and may refine surgical decision-making in borderline cases.<ref name="pmid36322642"/> Once a thoracic aortic aneurysm is identified, the patient should undergo cross-sectional imaging at 6 months to establish growth rate and annually thereafter if stable.

===Indications for Surgery===
* Rupture
* Symptomatic states
** Pain consistent with expansion or impending rupture
** Compression of adjacent organs
** Acute aortic syndromes ([[aortic dissection]], [[intramural haematoma]], [[penetrating aortic ulcer]])
* Significant [[aortic regurgitation]] in the setting of an ascending aortic aneurysm
* Rapid expansion (≥0.5 cm/year for thoracic aneurysms; ≥0.3 cm/year if confirmed on serial imaging in heritable aortopathy)
* Attainment of segment- and aetiology-specific size thresholds (see below)

====Size Thresholds for Elective Repair (2022 ACC/AHA Guideline)====
{| class="wikitable"
|-
! Aetiology !! Ascending aorta / root !! Descending thoracic aorta
|-
| Sporadic / degenerative || ≥5.5 cm (Class I) || ≥5.5 cm (Class I; TEVAR preferred if anatomically suitable)
|-
| Sporadic / degenerative ''with'' risk factors or at experienced aortic centre || ≥5.0 cm (Class IIa) || ≥5.0 cm (Class IIa)
|-
| [[Marfan syndrome]] || ≥5.0 cm (Class I); ≥4.5 cm if risk factors || Individualised; generally ≥5.5 cm
|-
| [[Loeys-Dietz syndrome]] (TGFBR1/TGFBR2) || ≥4.5 cm; ≥4.0 cm with high-risk features (Class IIa) || Individualised
|-
| [[Bicuspid aortic valve]] aortopathy || ≥5.5 cm (Class I); ≥5.0 cm with risk factors or at experienced centre (Class IIa) || —
|-
| Vascular [[Ehlers-Danlos syndrome]] || Individualised; lower thresholds || Individualised; lower thresholds
|}
''Risk factors triggering repair at smaller diameters include: family history of aortic dissection, rapid growth (≥0.5 cm/year), planned pregnancy, severe aortic valve regurgitation, short stature with cross-sectional area/height ratio >10 cm²/m, or concurrent cardiac surgery.''<ref name="pmid36322642"/>

====Bicuspid Aortic Valve Aortopathy — Special Considerations====
Approximately 50% of patients with [[bicuspid aortic valve]] (BAV) develop ascending aortic dilation. Key management considerations include:
* '''Phenotype-specific risk''': root phenotype (more common in young men) and Sievers type 0 fusion of right and left coronary cusps may be associated with greater dilation rates than the more common ascending (tubular) phenotype.<ref name="pmid36322642"/>
* '''Threshold of ≥5.5 cm''' for isolated BAV-associated aortopathy is Class I; '''≥5.0 cm''' is reasonable (Class IIa) at experienced aortic centres or with risk factors (family history of dissection, growth ≥0.3 cm/year, aortic coarctation, planned pregnancy, severe aortic stenosis or regurgitation).<ref name="pmid36322642"/>
* '''Concomitant aortic replacement''' should be considered when an ascending aorta of ≥4.5 cm is present at the time of aortic valve surgery (Class IIa, 2022 ACC/AHA).<ref name="pmid36322642"/>
* '''Family screening''': first-degree relatives of patients with BAV should be screened with [[transthoracic echocardiography]] (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>

===Surgery for Thoracic Aortic Aneurysm===
The choice of operation depends on:
* Underlying pathology and aetiology
* Extent of the disease proximally and distally
* Patient life expectancy and surgical risk
* Institutional and operator experience
* Desired anticoagulation status

====Ascending Aortic Aneurysms====
{| class="wikitable"
|-
! Anatomical scenario !! Preferred surgical approach
|-
| Ascending aorta with normal aortic valve, annulus and sinuses of Valsalva || Simple [[dacron]] supracoronary tube graft
|-
| Diseased aortic valve with normal sinuses and annulus || Separate [[aortic valve]] replacement plus supracoronary synthetic graft
|-
| Normal valve with aneurysmal sinuses and aortic insufficiency || Valve-sparing root replacement: (1) ''Remodelling'' (Yacoub) — resect sinus tissue and reconstruct with dacron graft; (2) ''Re-implantation'' (David) — reimplant the scalloped native valve within a dacron graft
|-
| Diseased aortic valve with diseased aortic root || Aortic root replacement (Bentall procedure): composite mechanical valved conduit (younger patients, requiring lifelong [[warfarin]]) or bioprosthetic valved conduit (older patients or contraindication to anticoagulation)
|-
| [[Marfan syndrome]] / heritable thoracic aortic disease || Valve-sparing aortic root replacement (David procedure preferred when leaflets are pliable) or composite valve graft if leaflets are diseased
|}

====Aortic Arch====
{| class="wikitable"
|-
! Extent of arch involvement !! Preferred surgical approach
|-
| Proximal arch (involving the lesser curve) with ascending aortic aneurysm || Hemiarch replacement under hypothermic circulatory arrest with antegrade cerebral perfusion
|-
| Total arch involvement || Total arch replacement with a branched graft (e.g., trifurcated graft) and selective antegrade cerebral perfusion
|-
| Arch + descending aorta involvement || Frozen elephant trunk (FET) procedure or staged hybrid arch repair
|}

Aortic arch endovascular repair has evolved with the introduction of single-, double-, and triple-branched arch devices. These remain investigational or restricted to experienced aortic centres but offer an alternative for high-risk patients with arch pathology. The Ishimaru zone classification (zones 0–4) is used to describe proximal landing zones and inform the need for supra-aortic debranching or branched endovascular devices.

====Descending Thoracic and Thoracoabdominal Aorta====
* [[Thoracic endovascular aortic repair]] (TEVAR) is the preferred modality for anatomically suitable descending thoracic aortic aneurysms (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>
* Open surgery is reserved for patients with anatomy unsuitable for endovascular repair, or those with connective tissue disorders in whom TEVAR durability is uncertain.
* '''Branched and fenestrated endovascular repair (B/FEVAR)''' is increasingly used at experienced aortic centres for thoracoabdominal aneurysms involving the visceral segment in patients who are high risk for open repair. Patient-specific custom-manufactured devices remain the standard, although off-the-shelf branched devices (e.g., t-Branch) are useful for urgent cases.
* Factors determining operative approach include age and comorbidities, aortic diameter and extent of lesion, anatomical suitability for endovascular repair (landing zones, access vessels, visceral vessel coverage), life expectancy, and presence of a connective tissue disorder.

===Surgical Management of Acute Aortic Syndromes===

====Acute Type A Aortic Dissection====
Acute Type A aortic dissection ('''ATAAD''') is a surgical emergency with an untreated mortality of approximately 1–2% per hour in the first 48 hours.<ref name="pmid36322642"/> Emergency open surgical repair is recommended for all patients with ATAAD irrespective of age unless prohibitive comorbidity exists (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>

Key principles of surgical strategy:
* '''Resection of the primary entry tear''' is the central goal.
* '''Hemiarch replacement''' is the most commonly performed adjunct when the entry tear is confined to the ascending aorta.
* '''Total arch replacement, with or without frozen elephant trunk (FET)''', is reasonable when the entry tear is in the arch, when the arch is aneurysmal, in young patients, in patients with connective tissue disease, or to promote favourable distal aortic remodelling.
* '''Aortic root management''': supracoronary ascending replacement is sufficient for an uninvolved root; root replacement (Bentall or valve-sparing David procedure) is required for root destruction, severe aortic regurgitation, or heritable aortopathy.
* '''Arterial cannulation''': axillary or innominate artery cannulation is preferred over femoral cannulation, providing antegrade perfusion and facilitating selective antegrade cerebral perfusion.
* '''Cerebral protection''': moderate hypothermic circulatory arrest (24–28 °C) with unilateral or bilateral selective antegrade cerebral perfusion is the contemporary standard.
* '''Malperfusion syndromes''' (cerebral, mesenteric, renal, limb) markedly increase operative mortality. Endovascular fenestration or branch vessel stenting prior to or during central aortic repair may be considered for severe organ malperfusion.

====Acute Type B Aortic Dissection====
Acute uncomplicated Type B aortic dissection is initially managed medically with anti-impulse therapy (target SBP <120 mmHg, HR <60 bpm). '''Pre-emptive TEVAR in the subacute phase (2–90 days)''' is reasonable in selected patients with high-risk imaging features (false lumen diameter ≥22 mm, primary entry tear ≥10 mm in the inner curvature, total aortic diameter ≥40–44 mm) to promote favourable aortic remodelling and reduce late aortic events, based on the INSTEAD-XL and ADSORB trials.<ref name="pmid23922146">{{cite journal |vauthors=Nienaber CA, Kische S, Rousseau H, Eggebrecht H, Rehders TC, Kundt G, Glass A, Scheinert D, Czerny M, Kleinfeldt T, Zipfel B, Labrousse L, Fattori R, Ince H |title=Endovascular repair of type B aortic dissection: long-term results of the randomized investigation of stent grafts in aortic dissection trial |journal=Circ Cardiovasc Interv |volume=6 |issue=4 |pages=407–16 |date=August 2013 |pmid=23922146 |doi=10.1161/CIRCINTERVENTIONS.113.000463 |url=}}</ref><ref name="pmid24962744">{{cite journal |vauthors=Brunkwall J, Kasprzak P, Verhoeven E, Heijmen R, Taylor P, Alric P, Canaud L, Janotta M, Raithel D, Malina W, Resch T, Eckstein HH, Ockert S, Larzon T, Carlsson F, Schumacher H, Classen S, Schaub P, Lammer J, Lönn L, Clough RE, Rampoldi V, Trimarchi S, Fabiani JN, Böckler D, Kotelis D, von Tenng-Kobligk H, Mangialardi N, Ronchey S, Dialetto G, Matoussevitch V |title=Endovascular repair of acute uncomplicated aortic type B dissection promotes aortic remodelling: 1 year results of the ADSORB trial |journal=Eur J Vasc Endovasc Surg |volume=48 |issue=3 |pages=285–91 |date=September 2014 |pmid=24962744 |doi=10.1016/j.ejvs.2014.05.012 |url=}}</ref>

'''Complicated acute Type B dissection''' (rupture, malperfusion, refractory pain or hypertension, rapid expansion) requires urgent intervention: TEVAR is the first-line treatment (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>

====Mycotic and Infected Aortic Aneurysms====
Infected (mycotic) thoracic aortic aneurysms warrant '''urgent surgical or endovascular intervention combined with prolonged targeted antimicrobial therapy''' (typically 6 weeks of intravenous therapy followed by long-term suppressive oral therapy). Open repair with extra-anatomic bypass and aortic resection has historically been the standard, but TEVAR is now recognized as a reasonable option as definitive therapy or as a bridge to open repair in unstable patients (Class IIa, 2022 ACC/AHA).<ref name="pmid36322642"/>

==2022 ACC/AHA Guidelines for the Diagnosis and Management of Aortic Disease — Surgical Treatment<ref name="pmid36322642"/>==

===Referral to Experienced Aortic Centres===
{| class="wikitable"
|-
| bgcolor="LightGreen" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen" | '''1.''' Patients with complex thoracic aortic disease requiring surgical intervention should be referred to experienced multidisciplinary aortic centres with demonstrated expertise in open and endovascular aortic repair to optimise operative outcomes.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}

===Asymptomatic Patients With Thoracic Aortic Aneurysm===
{| class="wikitable"
|-
| bgcolor="LightGreen" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen" | '''1.''' For asymptomatic patients with sporadic aneurysm of the aortic root or ascending aorta with diameter ≥5.5 cm, surgical repair is recommended.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|-
| bgcolor="LightGreen" | '''2.''' For asymptomatic patients with [[Marfan syndrome]] and aortic root diameter ≥5.0 cm, surgical repair is recommended.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|-
| bgcolor="LightGreen" | '''3.''' For asymptomatic patients with [[bicuspid aortic valve]] aortopathy and aortic root or ascending aortic diameter ≥5.5 cm, surgical repair is recommended.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}
{| class="wikitable"
|-
| bgcolor="LightYellow" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]]
|-
| bgcolor="LightYellow" | '''1.''' For asymptomatic patients with sporadic aneurysm of the aortic root or ascending aorta who meet specific risk criteria (rapid growth, family history of aortic dissection, cross-sectional area-to-height ratio >10 cm²/m, or planned pregnancy) and a diameter ≥5.0 cm, surgical repair at an experienced aortic centre is reasonable.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|-
| bgcolor="LightYellow" | '''2.''' For patients with [[Loeys-Dietz syndrome]] or confirmed TGFBR1 or TGFBR2 mutation, it is reasonable to proceed with aortic repair when the aortic diameter reaches 4.5 cm or greater (≥4.0 cm with high-risk features) by CTA external diameter measurement.<ref name="pmid36322642"/> ''(Level of Evidence: C-LD)''
|}

===Symptomatic Patients With Thoracic Aortic Aneurysm===
{| class="wikitable"
|-
| bgcolor="LightGreen" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen" | '''1.''' Patients with symptoms suggestive of expansion of a thoracic aortic aneurysm should be evaluated for prompt surgical intervention unless life expectancy from comorbid conditions is limited or quality of life is substantially impaired.<ref name="pmid36322642"/> ''(Level of Evidence: C-LD)''
|}

===Open Surgery for Ascending Aortic Aneurysm===
{| class="wikitable"
|-
| bgcolor="LightGreen" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen" | '''1.''' Separate valve and ascending aortic replacement is recommended in patients without significant aortic root dilatation, in elderly patients, or in younger patients with minimal dilatation who have aortic valve disease.<ref name="pmid36322642"/> ''(Level of Evidence: C-LD)''
|-
| bgcolor="LightGreen" | '''2.''' Patients with [[Marfan syndrome]], [[Loeys-Dietz syndrome]], or other heritable thoracic aortic disease who require aortic root replacement should be referred to experienced aortic centres.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}
{| class="wikitable"
|-
| bgcolor="LightYellow" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]]
|-
| bgcolor="LightYellow" | '''1.''' Valve-sparing aortic root replacement is reasonable in young patients with aortic root dilatation and tricuspid aortic valve leaflets without significant aortic insufficiency, when performed at experienced aortic centres.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}

===Descending Thoracic Aorta and Thoracoabdominal Aortic Aneurysms===
{| class="wikitable"
|-
| bgcolor="LightGreen" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen" | '''1.''' For patients with degenerative or traumatic aneurysms of the descending thoracic aorta exceeding 5.5 cm, [[saccular aneurysm|saccular aneurysms]], or postoperative [[pseudoaneurysm|pseudoaneurysms]], [[thoracic endovascular aortic repair]] (TEVAR) is recommended as the preferred treatment when anatomically feasible.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|-
| bgcolor="LightGreen" | '''2.''' For patients with chronic dissection, particularly if associated with a [[connective tissue disorder]], and a descending thoracic aortic diameter exceeding 5.5 cm, open repair is recommended when endovascular repair is not anatomically suitable or when a durable result is required.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}

===Coronary Revascularization Prior to Aortic Surgery===
{| class="wikitable"
|-
| bgcolor="LightYellow" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]]
|-
| bgcolor="LightYellow" | '''1.''' For patients undergoing surgery for thoracic aortic disease with significant left main or proximal multivessel coronary artery disease, concomitant coronary revascularization is reasonable.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}
{| class="wikitable"
|-
| bgcolor="LightCoral" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIb]]
|-
| bgcolor="LightCoral" | '''1.''' For patients undergoing low- or intermediate-risk surgery for thoracic aortic disease with clinically stable but significant coronary artery disease, the benefits of coronary revascularization are not well established.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}

===Choice of Anesthetic and Monitoring Techniques===
{| class="wikitable"
|-
| bgcolor="LightGreen" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen" | '''1.''' The choice of anaesthetic techniques and agents and patient monitoring techniques should be tailored to individual patient needs to facilitate surgical and perfusion techniques and the monitoring of haemodynamics and organ function.<ref name="pmid36322642"/> ''(Level of Evidence: C-LD)''
|}
{| class="wikitable"
|-
| bgcolor="LightYellow" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]]
|-
| bgcolor="LightYellow" | '''1.''' [[Transesophageal echocardiography]] is reasonable in all open surgical repairs of the [[thoracic aorta]] unless contraindicated, to assist with intraoperative haemodynamic monitoring, valvular assessment, and detection of complications.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}

===Spinal Cord Protection in Open and Endovascular Thoracic Aortic Repair===
{| class="wikitable"
|-
| bgcolor="LightGreen" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]]
|-
| bgcolor="LightGreen" | '''1.''' [[Cerebrospinal fluid]] drainage is recommended as a spinal cord protective strategy in open and endovascular thoracic aortic repair for patients at high risk of [[spinal cord ischaemia|spinal cord ischemic injury]].<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}
{| class="wikitable"
|-
| bgcolor="LightYellow" | [[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]]
|-
| bgcolor="LightYellow" | '''1.''' Spinal cord perfusion pressure optimisation using techniques such as proximal aortic pressure maintenance and distal aortic perfusion is reasonable as an integral part of the surgical, anaesthetic, and perfusion strategy in open and endovascular thoracic aortic repair for patients at high risk of spinal cord ischemic injury.<ref name="pmid36322642"/> ''(Level of Evidence: B-NR)''
|}

==Special Populations==

===Pregnancy===
* '''Pre-pregnancy counselling''' is recommended for all women with known thoracic aortic disease.
* '''Aortic root replacement before pregnancy''' is recommended for women with [[Marfan syndrome]] and an aortic root ≥4.5 cm (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>
* '''Caesarean delivery''' is recommended for women with an aortic diameter >4.5 cm in Marfan syndrome or in any patient with significant aortic dilation.
* '''Acute Type A dissection during pregnancy''': urgent surgical repair is required. In the third trimester, simultaneous Caesarean delivery before cardiopulmonary bypass is recommended; in the second trimester, the approach is individualised.

===Women===
Women have smaller aortas in absolute terms, and threshold-based criteria may underestimate rupture and dissection risk. Body surface area-indexed measurements (aortic size index, ASI) and height-indexed cross-sectional area-to-height ratio (>10 cm²/m) should be considered, particularly in women of short stature.<ref name="pmid36322642"/>

===Vascular Ehlers-Danlos Syndrome===
Open and endovascular intervention carries a markedly elevated risk of vascular complications due to tissue fragility. Surgery should be reserved for life-threatening indications and performed at centres with specific [[vascular Ehlers-Danlos syndrome|vEDS]] expertise. '''Celiprolol''' has been shown to reduce arterial events in vEDS and is recommended (BBEST trial).<ref name="pmid20825986">{{cite journal |vauthors=Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J, Fauret AL, Fiessinger JN, Germain DP, Georgesco G, Hulot JS, De Paepe A, Plauchu H, Jeunemaitre X, Laurent S, Boutouyrie P |title=Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial |journal=Lancet |volume=376 |issue=9751 |pages=1476–84 |date=October 2010 |pmid=20825986 |doi=10.1016/S0140-6736(10)60960-9 |url=}}</ref>

==Post-Operative Surveillance==
Patients who have undergone surgical or endovascular thoracic aortic repair require lifelong imaging surveillance to detect graft complications and disease progression in the unrepaired aorta.
* '''Baseline post-operative imaging''' (CTA preferred) within 30 days of repair.
* '''Surveillance CTA''' at 6 and 12 months for the first year, then annually if stable (Class I, 2022 ACC/AHA).<ref name="pmid36322642"/>
* '''After TEVAR''': closer surveillance for endoleak, stent migration, and retrograde Type A dissection; CTA at 1, 6, and 12 months, then annually.
* '''Genetic counselling and family screening''' (Class I) for all patients with non-traumatic thoracic aortic disease presenting before age 60 or with a positive family history.<ref name="pmid36322642"/>

==Aortic Centre and Surgeon Volume==
The 2022 ACC/AHA guideline introduced the concept of the '''multidisciplinary aortic centre''', defined by:
* Surgeon annual volume ≥30–40 elective open proximal aortic procedures
* Institutional volume ≥30–40 open and endovascular thoracic aortic procedures annually
* Mortality benchmarks: elective ascending aortic repair <5%, elective TEVAR <3%
* On-site availability of cardiac anaesthesia, perfusion, vascular surgery, neurology, and 24/7 imaging support<ref name="pmid36322642"/>

Referral to such centres for complex thoracic aortic disease is a Class I recommendation.

==References==
{{reflist|2}}

[[Category:Cardiac surgery]]
[[Category:Vascular surgery]]
[[Category:Aortic disease]]

Datopotamab deruxtecan-dlnk

2026-04-25T03:20:50Z

Anum Ijaz:

{{DrugProjectFormSinglePage
|authorTag={{AIJ}}
|genericName=DATROWAY
|aOrAn=a
|drugClass=Trop-2-directed antibody and topoisomerase inhibitor conjugate
|indicationType=treatment of EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC).
|adverseReactions=The most common adverse reactions (≥20%), including laboratory abnormalities, in patients with:
EGFR-mutated NSCLC were stomatitis, nausea, alopecia, fatigue, decreased hemoglobin, decreased lymphocytes, constipation, increased calcium, increased AST, decreased white blood cell count, increased lactate dehydrogenase, musculoskeletal pain, decreased appetite, increased ALT, and rash.
HR-positive, HER2-negative breast cancer were stomatitis, nausea, fatigue, decreased leukocytes, decreased calcium, alopecia, decreased lymphocytes, decreased hemoglobin, constipation, decreased neutrophils, dry eye, vomiting, increased ALT, keratitis, increased AST, and increased alkaline phosphatase.
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=DATROWAY is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of:

1. '''Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC)'''
DATROWAY is indicated for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who have received prior EGFR-directed therapy and platinum-based chemotherapy.

2. '''Unresectable or Metastatic, HR-Positive, HER2-Negative Breast Cancer'''
DATROWAY is indicated for the treatment of adult patients with unresectable or metastatic, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or me

'''Recommended Dosage'''

The recommended dosage of DATROWAY is 6 mg/kg (up to a maximum of 540 mg for patients ≥90 kg) administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

'''Premedication, Concomitant Medications, and Required Eye Care'''

Conduct an ophthalmic exam including visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy at initiation of DATROWAY, annually while on treatment, at end of treatment, and as clinically indicated.
Monitor patients for infusion-related reactions in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 1 hour for the first 2 cycles of DATROWAY infusions. If there are no infusion-related reactions observed, monitor patients for at least 30 minutes for all subsequent cycles of infusions.

'''Dosage Modifications'''

The recommended dose reduction levels for adverse reactions are described below:
1. First dose: 4 mg/kg (up to a maximum of 360 mg for patients ≥90 kg)
2. Second dose:3 mg/kg (up to a maximum of 270 mg for patients ≥90 kg)
3. Third dose: Permanently discontinue
Do not re-escalate the DATROWAY dose after a dose reduction. Permanently discontinue DATROWAY in patients who are unable to tolerate 3 mg/kg intravenously once every 3 weeks.

|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Datopotamab deruxtecan-dlnk in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Datopotamab deruxtecan-dlnk in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Datopotamab deruxtecan-dlnk in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Datopotamab deruxtecan-dlnk in pediatric patients.
|contraindications=None.
|warnings=
====Interstitial Lung Disease/Pneumonitis====

DATROWAY can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis.

'''Locally Advanced or Metastatic NSCLC'''

* In the pooled safety population of 484 patients with NSCLC from TROPION-Lung01, TROPION-Lung05, and TROPION-PanTumor01, ILD/pneumonitis occurred in 7% of patients treated with DATROWAY, including 0.6% of patients with Grade 3 and 0.4% with Grade 4. There were 8 (1.7%) fatal cases. The median time to onset for ILD was 1.4 months (range: 0.2 months to 9 months). Eleven patients (2.3%) had DATROWAY withheld and 20 patients (4.1%) permanently discontinued DATROWAY due to ILD/pneumonitis. Systemic corticosteroids were required in 79% (26/33) of patients with ILD/pneumonitis. ILD/pneumonitis resolved in 45% of patients.

'''Unresectable or Metastatic Breast Cancer'''

* In the pooled safety population of 443 patients with breast cancer from TROPION-Breast01 and TROPION-PanTumor01, ILD/pneumonitis occurred in 3.6% of patients treated with DATROWAY, including 0.7% of patients with Grade 3. There was one fatal case (0.2%). The median time to onset for ILD was 2.8 months (range: 1.1 months to 10.8 months). Four patients (0.9%) had DATROWAY withheld and 7 patients (1.6%) permanently discontinued DATROWAY due to ILD/pneumonitis. Systemic corticosteroids were required in 60% (9/15) of patients with ILD/pneumonitis. ILD/pneumonitis resolved in 40% of patients.

* Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever) during treatment with DATROWAY. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

====Ócular Adverse Effects====

* DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision.

* In the pooled safety population, ocular adverse reactions occurred in 36% of patients treated with DATROWAY. Twenty patients (2.2%) experienced Grade 3 ocular adverse reactions, which included keratitis, dry eye, and blurred vision, and one patient experienced a Grade 4 ocular adverse reaction of conjunctival hemorrhage. The most common (≥5%) ocular adverse reactions were dry eye (17%), keratitis (14%), and increased lacrimation (7%). The median time to onset for ocular adverse reactions was 2.3 months (range: 0.03 months to 23.2 months). Of the patients who experienced ocular adverse reactions, 39% had complete resolution, and 10% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade at last follow up). Ocular adverse reactions led to dosage interruption in 3.6% of patients, dosage reductions in 2.5% of patients, and permanent discontinuation of DATROWAY in 1% of patients.

* Advise patients to use preservative-free lubricant eye drops several times daily for prophylaxis. Advise patients to avoid use of contact lenses unless directed by an eye care professional.

* Refer patients to an eye care professional for an ophthalmic exam including visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy at treatment initiation, annually while on treatment, at end of treatment, and as clinically indicated.

====Stomatitis====

* DATROWAY can cause stomatitis, including mouth ulcers and oral mucositis.

* In the pooled safety population, stomatitis occurred in 63% of patients treated with DATROWAY, including 8% of patients with Grade 3 events and one patient with a Grade 4 reaction. The median time to first onset of stomatitis was 0.5 months (range: 0.03 months to 18.6 months). Stomatitis led to dosage interruption in 6% of patients, dosage reductions in 11% of patients, and permanent discontinuation of DATROWAY in 0.5% of patients.

* In patients who received DATROWAY in TROPION-Breast01, 39% used a mouthwash containing corticosteroid for management or prophylaxis of stomatitis/oral mucositis at any time during the treatment.

* Monitor patients for signs and symptoms of stomatitis. If stomatitis occurs, increase the frequency of mouthwash and administer other topical treatments as clinically indicated.

====Embryo-Fetal Toxicity====

* Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd is genotoxic and affects actively dividing cells

* Advise patients of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose.

Add table for dosage modifications in this section.
|clinicalTrials=
====Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer====

* The safety of DATROWAY was evaluated in 125 patients with EGFR-mutated NSCLC who received DATROWAY 6 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity in '''TROPION-Lung05''' and '''TROPION-Lung01''' as well as '''TROPION-PanTumor01''' (NCT03401385). Among these patients, the median duration of treatment was 6.1 months (range 0.7 months to 41.7 months).

* The median age was 63 years (range: 36 to 81), 56% of patients were <65 years, 62% of patients were female; 66% were Asian, 26% were White, 0.8% were Black, 6% were other races; and 2.4% were of Hispanic ethnicity.
* Serious adverse reactions occurred in 26% of patients who received DATROWAY. Serious adverse reactions in >1% of patients who received DATROWAY were COVID-19 (4%), stomatitis (2.4%), and pneumonia (1.6%). Fatal adverse reactions occurred in 1.6% of patients who received DATROWAY, due to death not otherwise specified.
* The most common (≥20%) adverse reactions, including laboratory abnormalities, were stomatitis, nausea, alopecia, fatigue, decreased hemoglobin, decreased lymphocytes, constipation, increased calcium, increased AST, decreased white blood cell count, increased lactate dehydrogenase, musculoskeletal pain, decreased appetite, increased ALT, and rash as listed in the table below:

====Unresectable or Metastatic, HR-Positive, HER2-Negative Breast Cancer====

'''TROPION-Breast01'''

* The safety of DATROWAY was evaluated in 360 patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who received at least one dose of DATROWAY 6 mg/kg in TROPION-Breast01. DATROWAY was administered by intravenous infusion once every three weeks. The median duration of treatment was 6.7 months (range: 0.7 months to 16.1 months) for patients who received DATROWAY.

* The most common (≥20%) adverse reactions, including laboratory abnormalities, were stomatitis, nausea, fatigue, decreased leukocytes, decreased calcium, alopecia, decreased lymphocytes, decreased hemoglobin, constipation, decreased neutrophils, dry eye, vomiting, increased ALT, keratitis, increased AST, and increased alkaline phosphatase. Add table 6

* Clinically relevant adverse reactions occurring in <10% of patients who received DATROWAY included infusion-related reactions (including bronchospasm), ILD/pneumonitis, headache, pruritus, dry skin, dry mouth, conjunctivitis, blepharitis, meibomian gland dysfunction, blurred vision, increased lacrimation, photophobia, visual impairment, skin hyperpigmentation, and madarosis.
Add table 7.
|postmarketing=There is limited information regarding Levacetylleucine Postmarketing Experience in the drug label.
|drugInteractions

* Clinical Studies and Model-Informed Approaches

No clinically significant differences in DXd pharmacokinetics were predicted when used concomitantly with itraconazole (strong CYP3A inhibitor) or ritonavir (dual OATP1B and CYP3A inhibitor).

* In Vitro Studies

CYP450 Enzymes: DXd does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A and does not induce CYP1A2, CYP2B6, or CYP3A.

UDP-Glucuronosyltransferase (UGT): DXd does not undergo significant metabolism by UGT enzymes.

Transporters Systems: DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP. DXd does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters.
|FDAPregCat=A
|useInPregnancyFDA=
'''Risk Summary'''

* Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd, is genotoxic and affects actively dividing cell. There are no available data on the use of DATROWAY in pregnant women to inform a drug-associated risk. Advise patients of the potential risks to a fetus.

* In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

'''Animal Data'''

* There were no animal reproductive or developmental toxicity studies conducted with datopotamab deruxtecan-dlnk.
|useInNursing=
* '''Lactation''':
There are no data regarding the presence of datopotamab deruxtecan-dlnk or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with DATROWAY and for 1 month after the last dose.
|useInPed=Safety and effectiveness of DATROWAY have not been established in pediatric patients.
|useInGeri=
* Of the 125 patients with EGFR-mutated NSCLC in TROPION-Lung05, TROPION-Lung01, TROPION-PanTumor01 treated with DATROWAY 6 mg/kg, 44% were ≥65 years of age and 10% were ≥75 years of age. No clinically meaningful differences in efficacy and safety were observed between patients ≥65 years of age versus younger patients.

* Of the 365 patients in TROPION-Breast01 treated with DATROWAY 6 mg/kg, 25% were ≥65 years of age and 5% were ≥75 years of age. Grade ≥3 and serious adverse reactions were more common in patients ≥65 years (42% and 25%, respectively) compared to patients <65 years (33% and 15%, respectively). In TROPION-Breast01, no other meaningful differences in safety or efficacy were observed between patients ≥65 years of age versus younger patients.
|useInRenalImpair=
* A higher incidence of ILD/pneumonitis has been observed in patients with mild and moderate renal impairment (creatinine clearance [CLcr] 30 to <90 mL/min). Monitor patients with renal impairment for increased adverse reactions, including respiratory reactions. No dosage adjustment is recommended in patients with mild to moderate renal impairment. The effect of severe renal impairment (CLcr <30 mL/min) on the pharmacokinetics of datopotamab deruxtecan-dlnk or DXd is unknown.
|useInHepaticImpair=
* No dosage adjustment is recommended in patients with mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST). Limited data are available in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST). Monitor patients with moderate hepatic impairment for increased adverse reactions [see Dosage and Administration (2.4)]. The recommended dosage of DATROWAY has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) [see Clinical Pharmacology.
|useInReproPotential='''Pregnancy Testing'''

* Verify pregnancy status of females of reproductive potential prior to initiation of DATROWAY.

'''Contraception'''

* Females

Advise females of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose.

* Males

Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose.

'''Infertility'''

* Based on findings in animal toxicity studies, DATROWAY may impair male and female reproductive function and fertility. The effects on reproductive organs in animals were irreversible
|administration=

* Reconstitute and further dilute DATROWAY prior to intravenous infusion. Use appropriate aseptic technique.

* DATROWAY (datopotamab deruxtecan-dlnk) is a hazardous drug. Follow applicable special handling and disposal procedures.

'''Reconstitution'''

* Reconstitute immediately before dilution.
* More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted DATROWAY solution required, and the number of vial(s) of * DATROWAY needed.
* Reconstitute each 100 mg vial using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection into each vial to obtain a final concentration of 20 mg/mL.
* Swirl the vial gently until completely dissolved. Do not shake.
* If not used immediately, refrigerate the reconstituted DATROWAY solution in the original vial at 2ºC to 8ºC (36°F to 46°F) for up to 48 hours from the time of reconstitution. Protect the vial from light. Do not freeze.
* The product does not contain a preservative. Discard unused reconstituted DATROWAY after 48 hours of refrigeration.

'''Dilution'''

* Withdraw the calculated amount from the vial(s) using a sterile syringe. Inspect for particulate matter and discoloration prior to administration. The reconstituted solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.
* Dilute the calculated volume of reconstituted DATROWAY in an infusion bag containing 100 mL of 5% Dextrose Injection. DO NOT use Sodium Chloride Injection. DATROWAY is compatible with an infusion bag made of polyvinylchloride or polyolefin (polypropylene or copolymer of ethylene and propylene).
* Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
* Cover the infusion bag to protect from light.
* If not used immediately, store at room temperature at up to 25ºC (77°F) for up to 4 hours including preparation or in a refrigerator at 2ºC to 8ºC (36°F to 46°F) for up to 24 hours. Do not freeze.
* Discard any unused portion left in the vial.

'''Administration'''

* The maximum time from reconstitution of the vial through the end of administration should not exceed 48 hours. Discard if storage time exceeds these limits.
* If the prepared infusion solution was stored refrigerated at 2ºC to 8ºC (36°F to 46°F), allow the solution to reach room temperature prior to administration, protected from light.
* Inspect for particulate matter and discoloration prior to administration.
* Administer DATROWAY as an intravenous infusion only with an infusion line and tubing set made of polyvinyl chloride, polybutadiene or low-density polyethylene.
* Administer DATROWAY with a 0.2-micron in-line polytetrafluoroethylene, polyethersulfone or nylon 66 filter.
* Do NOT administer as an intravenous push or bolus.
* Cover the infusion bag to protect from light during administration.
* Do not mix DATROWAY with other drugs or administer other drugs through the same intravenous line.
* Instruct the patient to hold ice chips or ice water in the mouth throughout the infusion of DATROWAY.
'''First infusion''': Administer infusion over 90 minutes. Observe patients during the infusion and for at least 1 hour following the initial dose for signs or symptoms of infusion-related reactions.
'''Second Infusion''': If first infusion was tolerated, administer second infusion over 30 minutes. Observe patients during the infusion and for at least 1 hour after infusion.
Subsequent Infusions: Administer infusion over 30 minutes if prior infusions were tolerated. Observe patients during the infusion and for at least 30 min after infusion.
|monitoring=Monitoring for Datroway and management for adverse reactions is listed in the table below:

Table 3
|mechAction=
* Datopotamab deruxtecan-dlnk, is a Trop-2-directed antibody-drug conjugate. The antibody is a humanized anti-Trop2 IgG1. The small molecule, DXd, is a topoisomerase I inhibitor attached to the antibody by a cleavable linker. Following binding to Trop-2 on cells, including tumor cells, datopotamab deruxtecan-dlnk undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable DXd causes DNA damage and apoptotic cell death. Datopotamab deruxtecan-dlnk had anti-tumor activity in mouse models of lung cancer including EGFR-mutated and breast cancer.
|structure=
* DATROWAY (datopotamab deruxtecan-dlnk) for injection is a sterile, white to yellowish white, preservative-free lyophilized powder in single-dose vials. Each vial delivers 100 mg of datopotamab deruxtecan-dlnk, L-histidine (3.88 mg), L-histidine hydrochloride monohydrate (5.25 mg), polysorbate 80 (1.50 mg), and sucrose (450 mg). Following reconstitution with 5 mL of Sterile Water for Injection, USP, the resulting concentration of datopotamab deruxtecan-dlnk is 20 mg/mL with a pH of 6.0. The resulting solution is administered by intravenous infusion following dilution.

add image
|PD=
* Datopotamab deruxtecan-dlnk time course of pharmacodynamic response is unknown.

* Exposure-Response Relationships

* A relationship between datopotamab deruxtecan-dlnk exposure and efficacy has not been fully characterized in breast cancer or EGFR-mutated NSCLC.

* In the pooled population of NSCLC (including EGFR-mutated NSCLC) and breast cancer patients, higher datopotamab deruxtecan-dlnk systemic exposure is associated with a higher incidence rate of serious adverse reactions, dosage interruptions, dose reductions, stomatitis/oral mucositis, ocular adverse reactions, and Grade ≥3 adverse reactions.

'''Cardiac Electrophysiology'''

* At datopotamab deruxtecan-dlnk doses up to 10 mg/kg (1.7 times the recommended dose), mean increase in the QTc interval >20 ms was not observed.
|PK=
* Datopotamab deruxtecan-dlnk and DXd exposure after the first dose of the approved recommended dosage of cycle 1 are provided in Table 8. Datopotamab deruxtecan-dlnk and released DXd maximum concentration (Cmax) and area under the time-concentration curve (AUC) increases proportionally over a dose range of 4 mg/kg to 10 mg/kg (approximately 0.7 to 1.7 times the approved recommended dosage). No clinically significant datopotamab deruxtecan-dlnk accumulation occurs between cycles 1 and 3.

Table 8

====Distribution====

* Datopotamab deruxtecan-dlnk mean steady state volume of distribution is 3.5 (23%) L.

* DXd plasma protein binding is approximately 98% and the blood-to-plasma concentration ratio is 0.6 in vitro.

====Elimination====

* The datopotamab deruxtecan-dlnk median elimination half-life (t1/2) is 4.8 days (1.0, 8.2) and the released DXd median apparent t1/2 is approximately 5.5 days (3.2, 8.8). * The estimated datopotamab deruxtecan-dlnk clearance is 0.6 (31.5%) L/day.

====Metabolism====

* Datopotamab deruxtecan-dlnk undergoes intracellular cleavage by lysosomal enzymes to release DXd.

* The humanized Trop-2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

* In vitro, DXd is primarily metabolized by CYP3A4.

====Specific Populations====

* The mean volume of distribution and clearance of datopotamab deruxtecan-dlnk and DXd increase with increasing body weight (36 kg to 156 kg).

* No clinically significant differences in the pharmacokinetics of datopotamab deruxtecan-dlnk or DXd were observed based on age (26 to 86 years), race (Asian, White, or Black), sex, mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), or mild to moderate renal impairment (CLcr 30 to <90 mL/min).

* The pharmacokinetics of datopotamab deruxtecan-dlnk in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST) was comparable to patients with normal hepatic function (total bilirubin and AST ≤ULN). The steady state average DXd AUC was 2.4-fold higher in patients with moderate hepatic impairment compared to patients with normal hepatic function. The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST) or severe renal impairment (CLcr <30 mL/min) on datopotamab deruxtecan-dlnk or DXd pharmacokinetics is unknown.

'''Immunogenicity'''
There is insufficient information from TROPION-Breast01, TROPION-Lung01, and TROPION-Lung05 to characterize the anti-drug antibody response to datopotamab deruxtecan-dlnk and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of datopotamab deruxtecan-dlnk products.
|nonClinToxic=Carcinogenesis, Mutagenesis, Impairment of Fertility
* Carcinogenicity studies have not been conducted with datopotamab deruxtecan-dlnk.

* The topoisomerase inhibitor component of datopotamab deruxtecan-dlnk, DXd, was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.

* Dedicated fertility studies have not been conducted with datopotamab deruxtecan-dlnk. In a 3-month repeat-dose toxicity study, intravenous administration of datopotamab deruxtecan-dlnk once every 3 weeks in rats resulted in decreased weights in the testes and epididymides, degeneration of the germinal epithelium and atrophy of seminiferous tubules in testes, and cell debris, decreased number of sperm, and single-cell necrosis of the ductal epithelium in epididymides at 200 mg/kg (approximately 29 times the human recommended dose of 6 mg/kg based on AUC). Findings in female rats included increased atretic follicles in the ovary and single cell necrosis of mucosal epithelium in the vagina at 200 mg/kg. These findings, except for the lesions in the testis and epididymis, were not observed after a 2-month recovery period.
|clinicalStudies=
'''Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer'''

* The efficacy of DATROWAY was evaluated in a pooled subgroup of patients with locally advanced or metastatic EGFR-mutated NSCLC who were enrolled across two clinical studies: TROPION-Lung05 and TROPION-Lung01.

* TROPION-Lung05 (NCT04484142) was a global, multicenter, single-arm, open-label trial in patients with previously treated NSCLC with an actionable genomic alteration and TROPION-Lung01 (NCT04656652) was a global, multicenter, randomized, active-controlled, open-label trial in patients with previously treated NSCLC with or without an actionable genomic alteration. For both trials, eligible patients with EGFR-mutated NSCLC must have previously received an EGFR-directed therapy and platinum-based chemotherapy. Patients with a history of ILD/pneumonitis requiring treatment with steroids, ongoing ILD/pneumonitis, or clinically significant corneal disease at screening were ineligible. Patients who had brain metastases that were untreated and symptomatic were also ineligible. Patients received DATROWAY 6 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression.

* For the pooled efficacy population, the major efficacy outcome measure was overall response rate (ORR) by BICR per RECIST v1.1. An additional efficacy outcome was duration of response (DOR) by BICR.

* Efficacy was assessed in 114 patients with EGFR-mutated NSCLC. The median age was 63 years (range 36 to 81); 43% were ≥65 years of age; 63% were female; 70% were Asian and 22% were White; 1.8% were of Hispanic/Latino ethnicity; 68% had ECOG PS of 1 and 32% had ECOG PS of 0; and 33% had brain metastases at baseline. Fifty-three percent (53%) of patients had tumors with exon 19 deletions, 34% had exon 21 L858R mutations, 28% had T790M mutations, 2.6% had exon 20 insertion mutations and 14% had other EGFR mutations. Four percent (4.4%) of patients received one prior line of systemic therapy, 39% received two prior lines of systemic therapy, and 57% received three or more prior lines of systemic therapy in the locally advanced or metastatic setting. All patients received prior EGFR-directed therapy including 84% receiving prior osimertinib; 99% received prior platinum-based chemotherapy and 28% received prior anti-PD-1/ PD-L1 therapy.

Add table 9

'''Unresectable or Metastatic, HR-Positive, HER2-Negative Breast Cancer'''
'''TROPION-Breast01'''

* The efficacy of DATROWAY was evaluated in TROPION-Breast01 (NCT05104866), a multicenter, open-label, randomized trial of 732 patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer. Eligible patients must have progressed on and deemed not suitable for further endocrine therapy. Patients were required to have received 1 or 2 lines of prior chemotherapy in the unresectable or metastatic disease setting. Patients were excluded for a history of ILD/pneumonitis requiring treatment with steroids, ongoing ILD/pneumonitis, clinically active brain metastases, or clinically significant corneal disease at screening. Patients were also excluded for ECOG performance status >1. Randomization was stratified by previous lines of chemotherapy (one or two), prior treatment with a CDK4/6 inhibitor (yes or no), and geographical region.

* A total of 732 patients were randomized 1:1 to receive either DATROWAY 6 mg/kg (N=365) by intravenous infusion every 3 weeks or investigator's choice of chemotherapy (N=367) until unacceptable toxicity or disease progression. Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (60%), capecitabine (21%), vinorelbine (10%), or gemcitabine (9%).

* The major efficacy outcomes were progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 and overall survival (OS). Additional efficacy outcomes included confirmed objective response rate (ORR) and duration of response (DOR) by BICR.

* The median age was 55 years (range 28-86); 22% were ≥65 years; 99% were female; 48% were White, 41% were Asian, 1.5% were Black or African American, and 11% were of Hispanic/Latino ethnicity; 57% had ECOG PS of 0 and 42% had ECOG PS of 1; 97% had visceral disease, 72% had liver metastases, and 8% had stable brain metastases.

* Sixty percent (60%) of patients received prior endocrine therapy in the (neo)adjuvant setting, and 89% received prior endocrine therapy in the unresectable or metastatic setting. Eighty-three percent (83%) of patients had prior treatment with a CDK4/6 inhibitor. All patients received prior chemotherapy regimens in the unresectable or metastatic setting (81% received prior taxanes; 64% received prior anthracyclines). Sixty-two percent (62%) of patients had 1 prior chemotherapy regimen and 38% of patients had 2 prior chemotherapy regimens for treatment of unresectable or metastatic disease.

* The study demonstrated a statistically significant improvement in PFS in patients randomized to DATROWAY compared to chemotherapy.

Table 10
|howSupplied=How Supplied

* DATROWAY (datopotamab deruxtecan-dlnk) for injection is a white to yellowish white lyophilized powder supplied as:

* Carton Contents : One 100 mg single-dose vial
* NDC : NDC 65597-801-01
|storage=Storage and Handling

* Store vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light until time of reconstitution. Do not freeze. Do not shake the reconstituted or diluted solution.
[[File:Datopotamab display panel.jpeg|400px|thumb|right|Principle Display Panel]]

* DATROWAY (datopotamab deruxtecan-dlnk) is a hazardous drug. Follow applicable special handling and disposal procedures.
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Medication Guide).

'''Interstitial Lung Disease/Pneumonitis'''

* Inform patients of the risks of severe or fatal ILD. Advise patients to contact their healthcare provider immediately for any of the following: cough, shortness of breath, fever, or other new or worsening respiratory symptoms.
'''Ocular Adverse Reactions'''

* Inform patients about the need for eye exams at initiation and during treatment with DATROWAY .
* Advise patients to contact their healthcare provider if they experience any eye symptoms.
* Advise patients to use preservative-free lubricating eye drops several times daily and to avoid use of contact lenses during treatment with DATROWAY.

'''Stomatitis'''

* Inform patients of the risk of stomatitis. Advise patients to contact their healthcare provider if they experience any symptoms.
* Inform patients to use a steroid-containing mouthwash for prophylaxis and treatment of stomatitis.
* Instruct patients to hold ice chips or ice water in their mouth throughout the infusion of DATROWAY.

'''Embryo-Fetal Toxicity'''

* Inform female patients of the potential risk to a fetus. Advise female patients to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose
* Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose.

'''Lactation'''

Advise women not to breastfeed during treatment and for 1 month after the last dose of DATROWAY .

'''Infertility'''

* Advise males and females of reproductive potential that DATROWAY may impair fertility.
|alcohol=Alcohol-Datopotamab deruxtecan-dlnk interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=DATROWAY
|lookAlike=There is limited information regarding Levacetylleucine Look-Alike Drug Names in the drug label.
}}