Version May 2024
Dosage guidance:
Safety: Evaluate fasting blood glucose and HbA1c and optimize blood glucose prior to capivasertib initiation.
Clinical considerations: Select patients for therapy based on the presence of one or more genetic alterations of PIK3CA, AKT1, and/or PTEN in tumor tissue.
Breast cancer, locally advanced or metastatic, HR-positive, HER2-negative, PIK3CA, AKT1, and/or PTEN-altered: Note: For pre- and peri-menopausal patients, also administer a luteinizing hormone-releasing hormone (LHRH) agonist (according to current clinical practice standards) (Ref). For males, consider administering an LHRH agonist (according to current clinical practice standards).
Oral: 400 mg twice daily (~12 hours apart) for 4 consecutive days, followed by 3 days off (administer capivasertib on days 1 to 4 of each week); in combination with fulvestrant; continue until disease progression or unacceptable toxicity (Ref).
Missed doses: If a dose is missed within 4 hours of the scheduled time, administer the missed dose. If a dose is missed by more than 4 hours of the scheduled time, skip the dose and administer the next dose at its usual scheduled time. If a dose is vomited, do not administer an additional dose; administer the next dose at its usual scheduled time.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl 15 to <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.
Hepatic impairment prior to treatment initiation:
Mild impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment is necessary.
Moderate impairment (bilirubin >1.5 to 3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (effect is not fully characterized). Capivasertib exposure may be increased; monitor for adverse reactions.
Severe impairment (total bilirubin >3 times ULN with any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
|
Dose level |
Capivasertib dose and schedule |
|---|---|
|
Initial (usual) dose |
400 mg twice daily for 4 days, followed by 3 days off. |
|
First dose reduction |
320 mg twice daily for 4 days, followed by 3 days off. |
|
Second dose reduction |
200 mg twice daily for 4 days, followed by 3 days off. |
|
Permanently discontinue if unable to tolerate the second dose reduction. | |
|
Adverse reaction |
Severity |
Capivasertib dosage modificationa |
|---|---|---|
|
a Fulvestrant may also require dosage modification. | ||
|
b FBG = fasting blood glucose. | ||
|
Dermatologic toxicity: Cutaneous adverse reactions |
Any |
Early consultation with a dermatologist is recommended. May require corticosteroids (topical or systemic, depending on the severity) to manage. |
|
Grade 2 |
Withhold capivasertib until recovery to ≤ grade 1. Resume capivasertib at the same dose. Persistent or recurrent grade 2 toxicity: Reduce capivasertib by one dose level. | |
|
Grade 3 |
Withhold capivasertib until recovery to ≤ grade 1. Resolution ≤28 days after interruption: Resume capivasertib at the same dose. Resolution >28 days after interruption: Resume capivasertib at one lower dose level. Recurrent grade 3 toxicity: Permanently discontinue capivasertib. | |
|
Grade 4 |
Permanently discontinue capivasertib. | |
|
GI toxicity: Diarrhea |
Any |
May require antidiarrheal medications to manage symptoms. Advise patients to increase oral fluids and start antidiarrheal treatment at the first sign of diarrhea. |
|
Grade 2 |
Withhold capivasertib until recovery to ≤ grade 1. Resolution ≤28 days after interruption: Resume capivasertib at the same or at one lower dose level as clinically indicated. Resolution >28 days after interruption: Resume capivasertib at one lower dose level as clinically indicated. Recurrence: Reduce capivasertib by one dose level. | |
|
Grade 3 |
Withhold capivasertib until recovery to ≤ grade 1. Resolution ≤28 days after interruption: Resume capivasertib at the same or at one lower dose level as clinically indicated. Resolution >28 days after interruption: Permanently discontinue capivasertib. | |
|
Grade 4 |
Permanently discontinue capivasertib. | |
|
Hyperglycemia |
Any |
Consider consultation with a health care practitioner with expertise in hyperglycemia management. Counsel patients on lifestyle modifications. |
|
FBGb > ULN to 160 mg/dL or FBG > ULN to 8.9 mmol/L or HbA1c >7% |
Consider initiation or intensification of oral antidiabetic therapy. | |
|
FBG 161 to 250 mg/dL or FBG 9 to 13.9 mmol/L |
Withhold capivasertib until FBG decreases to ≤160 mg/dL (or ≤8.9 mmol/L). Resolution ≤28 days after interruption: Resume capivasertib at the same dose. Resolution >28 days after interruption: Resume capivasertib at one lower dose level. | |
|
FBG 251 to 500 mg/dL or FBG 14 to 27.8 mmol/L |
Withhold capivasertib until FBG decreases to ≤160 mg/dL (or ≤8.9 mmol/L). Resolution ≤28 days after interruption: Resume capivasertib at one lower dose level. Resolution >28 days after interruption: Permanently discontinue capivasertib. | |
|
FBG >500 mg/dL or FBG >27.8 mmol/L or Life-threatening hyperglycemia sequelae at any FBG level |
If FBG is ≤500 mg/dL (or ≤27.8 mmol/L) within 24 hours: Follow the guidance in this table for the relevant FBG. Life-threatening hyperglycemia sequelae or if FBG persists at ≥500 mg/dL after 24 hours: Permanently discontinue capivasertib.
| |
|
Other adverse reactions |
Grade 2 |
Withhold capivasertib until recovery to ≤ grade 1. Resume capivasertib at the same dose. |
|
Grade 3 |
Withhold capivasertib until recovery to ≤ grade 1. Resolution ≤28 days after interruption: Resume capivasertib at the same dose. Resolution >28 days after interruption: Resume capivasertib at one lower dose level. | |
|
Grade 4 |
Permanently discontinue capivasertib. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in combination with fulvestrant in adults.
>10%:
Dermatologic: Dermatologic disorder (56%; including allergic dermatitis, dermal ulcer, dermatitis, eczema, erythema multiforme, erythematous rash, erythema of skin, maculopapular rash, palmar-plantar erythrodysesthesia, papular rash, pruritus, purpuric rash, skin discoloration, skin fissure, skin rash, urticaria, xeroderma)
Endocrine & metabolic: Decreased serum calcium (corrected: 19%), decreased serum potassium (17%), hyperglycemia (19%; including severe hyperglycemia), increased serum triglycerides (30%)
Gastrointestinal: Decreased appetite (17%), diarrhea (77%; grades 3/4: 12%), nausea (35%; grades 3/4: 1%), stomatitis (25%; grades 3/4: 2%), vomiting (21%; grades 3/4: 2%)
Genitourinary: Urinary tract infection (14%)
Hematologic & oncologic: Decreased neutrophils (25%; grades 3/4: 2%), decreased platelet count (12%; grades 3/4: 2%), leukopenia (35%; grades 3/4: <1%), lymphocytopenia (49%; grades 3/4: 11%)
Hepatic: Increased serum alanine aminotransferase (23%)
Nervous system: Fatigue (38%), headache (17%)
Renal: Increased serum creatinine (19%), kidney impairment (11%; including acute kidney injury, decreased estimated GFR [eGFR], kidney failure, proteinuria)
1% to 10%:
Gastrointestinal: Dysgeusia (<10%), dyspepsia (<10%)
Hematologic & oncologic: Anemia (<10%), second primary malignant neoplasm (1%)
Hypersensitivity: Hypersensitivity reaction (<10%; including anaphylaxis, severe hypersensitivity reaction [1%])
Respiratory: Pneumonia (3%)
Miscellaneous: Fever (<10%)
<1%:
Endocrine & metabolic: Diabetic ketoacidosis
Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms
Severe hypersensitivity to capivasertib or any component of the formulation.
Concerns related to adverse effects:
• Dermatologic toxicity: Cutaneous adverse reactions, which may be severe, have occurred with capivasertib. Reactions have included erythema multiforme (EM), palmar-plantar erythrodysesthesia, and drug reaction with eosinophilia and systemic symptoms (DRESS). Cutaneous adverse reactions occurred in over half of capivasertib-treated patients; grade 3 or 4 cutaneous adverse events were reported. EM and DRESS occurred in a small percentage of patients. The median time to onset of cutaneous adverse reactions was 13 days (range: 1 to 575 days). Cutaneous adverse reactions resulted in dose modifications in some patients. May require management with either topical or systemic corticosteroids (depending on the severity). The median time to improvement for ≥ grade 2 cutaneous adverse reaction (with at least 1 grade improvement), from the first event was 12 days (range: 2 to 544 days).
• GI toxicity: Severe diarrhea associated with dehydration has occurred in capivasertib-treated patients. Diarrhea occurred in nearly three-fourths of patients; grade 3 or 4 diarrhea events were reported. The median time to first occurrence was 8 days (range: 1 to 519 days). May require antidiarrheal medications to manage symptoms; over half of capivasertib-treated patients required antidiarrheal medications in the clinical trial. Dose modifications due to diarrhea were required in some patients. In patients with ≥ grade 2 diarrhea (with at least 1 grade improvement), the median time to improvement from the first event was 4 days (range: 1 to 154 days).
• Hyperglycemia: Severe hyperglycemia, associated with ketoacidosis, has occurred in capivasertib-treated patients. The safety of capivasertib has not been established in patients with type I diabetes or diabetes requiring insulin; patients with insulin-dependent diabetes were excluded from the clinical study. Hyperglycemia has occurred in nearly 20% of patients. Grade 3 (insulin therapy initiated; hospitalization indicated) or grade 4 (life-threatening consequences; urgent intervention indicated) hyperglycemia events occurred in a small percentage of patients; diabetic ketoacidosis and diabetic metabolic decompensation occurred rarely. Dose modification for hyperglycemia was required in some cases. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367 days). Nearly half of patients who experienced hyperglycemia required antihyperglycemic medications (eg, insulin, metformin); of those who required antihyperglycemic medications during capivasertib treatment, a majority remained on these medications at capivasertib treatment discontinuation (or at last follow up). Prior to initiating capivasertib, inform patients about the potential for hyperglycemia and to immediately contact their health care professional if hyperglycemia symptoms (eg, excessive thirst, more frequent urination, higher urination volume, increased appetite with weight loss) occur. Patients with risk factors for hyperglycemia include those with obesity (BMI ≥30 kg/m2), elevated fasting blood glucose >160 mg/dL (>8.9 mmol/L), HbA1c ≥ ULN, with the use of concomitant systemic corticosteroids, or with intercurrent infections. Hyperglycemia may require consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counseling on lifestyle modifications.
Special populations:
• Older adults: A higher incidence of grade 3 to 5 adverse reactions and dosage modifications were required in patients ≥65 years of age (compared to patients <65 years of age).
Other warnings/precautions:
• Appropriate use: Select patients for therapy based on the presence of one or more genetic alterations of PIK3CA, AKT1, and/or PTEN in tumor tissue. Information on tests approved for the detection of PIK3CA, AKT1, and PTEN alterations is available at http://www.fda.gov/CompanionDiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Truqap: 160 mg, 200 mg
No
Tablets (Truqap Oral)
160 mg (per each): $429.79
200 mg (per each): $429.79
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Capivasertib is available through specialty pharmacies/distributors and various specialty institutions/accounts. Examples from the manufacturer may be found at https://www.truqaphcp.com/access-and-support.
Oral: Administer with or without food, approximately every 12 hours on scheduled days. Swallow whole; do not chew, crush, or split tablets. Do not administer tablets that are broken, cracked, or otherwise not intact.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Capivasertib may cause genotoxicity and reproductive toxicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Breast cancer, locally advanced or metastatic, hormone receptor-positive, human epidermal growth factor receptor 2-negative, PIK3CA, AKT1, and/or PTEN-altered: Treatment (in combination with fulvestrant) of locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in adults with one or more PIK3CA/AKT1/PTEN-alteration (as detected by an approved test) following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.
Capivasertib may be confused with cabozantinib, capecitabine, capmatinib, ceritinib, crizotinib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP3A4 (major), UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Capivasertib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Capivasertib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Capivasertib. Management: If capivasertib is combined with moderate CYP3A4 inhibitors, reduce the capivasertib dose to 320 mg twice daily for 4 days, followed by 3 days off. Monitor patients closely for adverse reactions. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Capivasertib. Management: Avoid concomitant use of capivasertib with strong CYP3A4 inhibitors when possible. If combined, reduce the capivasertib dose to 320 mg twice daily for 4 days, followed by 3 days off. Monitor patients closely for adverse reactions. Risk D: Consider therapy modification
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification
Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification
Tacrolimus (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification
Grapefruit may interact with capivasertib. Management: Patients should not consume grapefruit products during treatment with capivasertib.
Verify pregnancy status prior to use in patients who could become pregnant.
Patients who could become pregnant should use effective contraception during therapy and for 1 month after the last dose of capivasertib. Patients with partners who could become pregnant should also use effective contraception during therapy and for 4 months after the last capivasertib dose.
Capivasertib is used in combination with fulvestrant; also refer to the Fulvestrant monograph for additional information.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to capivasertib may cause fetal harm. In animal studies, adverse outcomes were observed with maternal doses less than the human exposure (based on AUC).
Capivasertib is used in combination with fulvestrant; also refer to the Fulvestrant monograph for additional information.
It is not known if capivasertib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding during treatment is not recommended by the manufacturer. Capivasertib is used in combination with fulvestrant; also refer to the Fulvestrant monograph for additional information.
Avoid grapefruit products.
PIK3CA, AKT1, and/or PTEN genetic alteration status in tumor tissue. Hepatic function (bilirubin, ALT, and AST) prior to treatment.
Hyperglycemia: Evaluate fasting blood glucose (FBG) and HbA1c prior to capivasertib initiation and periodically during therapy. Evaluate FBG at least every 2 weeks during the first month and at least once a month starting from the second month, prior to the scheduled capivasertib dose. During capivasertib treatment, monitor FBG more frequently in patients with a medical history of diabetes mellitus and in patients with risk factors for hyperglycemia such as obesity (BMI ≥30 kg/m2), elevated FBG of >160 mg/dL (>8.9 mmol/L), HbA1c ≥ ULN, with the use of concomitant systemic corticosteroids, or with intercurrent infections. Monitor HbA1c every 3 months. If a patient experiences hyperglycemia after initiating capivasertib, monitor FBG as clinically indicated, and at least twice weekly until FBG decreases to normal levels; during antihyperglycemic medication therapy, continue monitoring FBG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Verify pregnancy status prior to treatment initiation in patients who could become pregnant.
Monitor for signs/symptoms of cutaneous adverse reactions, diarrhea, and hyperglycemia; monitor for adverse reactions in patients with moderate hepatic impairment. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Capivasertib is a small molecule, potent, and selective kinase inhibitor of all 3 isoforms of serine/threonine protein kinase AKT (AKT1, AKT2 and AKT3) and inhibits phosphorylation of downstream AKT substrates (Howell 2022; Jones 2020). AKT activation in tumors is due to activation of upstream signaling pathways, mutations in AKT1, loss of phosphatase and tensin homolog (PTEN) function, as well as catalytic subunit alpha mutations of phosphatidylinositol 3-kinase (PIK3CA). Capivasertib reduced growth of breast cancer cell lines (in vitro) including those with relevant PIK3CA or AKT1 mutations or PTEN alteration. In animal models, capivasertib (± fulvestrant) inhibited tumor growth, including in estrogen receptor positive breast cancer models harboring PIK3CA, AKT1, and PTEN alterations.
Distribution: Vdss: 1,847 L.
Protein binding: 22%.
Metabolism: Hepatic; primarily via CYP3A4 and UGT2B7.
Bioavailability: 29%.
Half-life elimination: 8.3 hours.
Time to peak: ~1 to 2 hours.
Excretion: Feces (50%); urine (45%).
Clearance: 50 L/hour (at steady state); renal clearance was 21%.
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