Introduction

Mechanistic target of rapamycin kinase (mTOR) inhibitor; antineoplastic agent. Preparation of sirolimus formulated as albumin-bound particles.

Uses for Sirolimus, albumin-bound

Perivascular Epithelioid Cell Tumor (PEComa)

Treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

Designated an orphan drug by FDA for this use.

Sirolimus, albumin-bound Dosage and Administration

General

Pretreatment Screening

• Monitor potassium levels prior to starting albumin-bound sirolimus and implement potassium supplementation as medically indicated.

• Perform routine laboratory testing for assessment of glucose and CBC.

• Update vaccinations according to immunization guidelines prior to initiating albumin-bound sirolimus, if possible.

• Verify pregnancy status of females of reproductive potential prior to initiating albumin-bound sirolimus.

Patient Monitoring

• Perform routine laboratory testing for assessment of potassium, glucose, and CBC.

• Monitor for signs and symptoms of infection, including reactivation of latent viral infections.

• Monitor for signs and symptoms of bleeding due to the risk of hemorrhage.

• Monitor patients closely for signs and symptoms of infusion reactions during and following each albumin-bound sirolimus infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion.

Dispensing and Administration Precautions

• Albumin-bound sirolimus is a hazardous drug. Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

Administration

IV Administration

Administer by IV infusion.

Reconstitution

The lyophilized powder must be reconstituted to an injectable suspension prior to IV infusion.

Using aseptic technique, inject 20 mL of 0.9% sodium chloride injection slowly (over a minimum period of 1 minute) into the vial containing the lyophilized powder. Direct the flow of diluent toward the inside wall of the vial rather than directly on the lyophilized cake to avoid foaming. After addition of diluent, allow vial to sit for a minimum of 5 minutes to ensure thorough wetting of the lyophilized cake/powder. Then, gently swirl and/or invert vial (do not shake) for at least 2 minutes until the cake/powder is completely dissolved; avoid foaming. If foaming or clumping occurs, allow the reconstituted suspension to stand for at least 15 minutes until foaming subsides. Do not use if foaming or clumping is present after 1 hour.

The reconstituted sirolimus suspension has a final concentration of 5 mg/mL.

Transfer the calculated volume of reconstituted albumin-bound sirolimus to an empty PVC or polyolefin infusion bag without further dilution.

Visually inspect reconstituted albumin-bound sirolimus suspension in the infusion bag prior to administration. Discard reconstituted suspension if particulate matter, proteinaceous strands, or discoloration are observed.

Rate of Administration

Administer IV infusion over 30 minutes.

Dosage

Dosage of albumin-bound sirolimus is expressed in terms of sirolimus.

Adults

Perivascular Epithelioid Cell Tumor (PEComa) in Adults

IV

100 mg/m² as an IV infusion on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

Dosage Modifications for Adverse Reactions

Dosage interruption and/or reduction or discontinuance of therapy may be necessary based on severity of adverse reactions. See Table 1 for recommended dose reductions for adverse reactions and Table 2 for recommended dosage modifications/interventions for adverse effects.

Permanently discontinue albumin-bound sirolimus in patients who are unable to tolerate it after 3 dose reductions.

Dosage Modification for Concomitant Use with CYP3A4 and/or P-gp Inhibitors and Inducers

Reduce initial dosage to 56 mg/m² when used concomitantly with a moderate or weak cytochrome P-450 3A4 (CYP3A4) inhibitor.

Avoid concomitant use with strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors and inducers and grapefruit and grapefruit juice.

Special Populations

Hepatic Impairment

Patients with mild (total bilirubin ≤ULN, AST >ULN or total bilirubin >1 to 1.5×ULN, any AST): reduce initial dosage to 75 mg/m².

Patients with moderate hepatic impairment (total bilirubin >1.5 to 3×ULN, any AST): reduce initial dosage to 56 mg/m².

Closely monitor patients with hepatic impairment for increased toxicity. Avoid use in patients with severe hepatic impairment.

Contraindications

• History of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin.

Warnings/Precautions

Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, reported, most often within 8 weeks of treatment. Based on severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue.

Myelosuppression

Risk of myelosuppression including anemia, thrombocytopenia, and neutropenia.

Obtain blood counts at baseline and every 2 months for the first year of treatment and every 3 months thereafter, or more frequently if clinically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue.

Infections

Risk of infections. Infections such as urinary tract infections (UTI), upper respiratory tract infections, and sinusitis reported.

Monitor patients for infections, including opportunistic infections. Based on severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue.

Hypokalemia

Risk of hypokalemia.

Monitor potassium levels prior to starting therapy and implement potassium supplementation as medically indicated. Based on severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue

Hyperglycemia

Risk of hyperglycemia.

Monitor fasting serum glucose prior to starting albumin-bound sirolimus. During treatment, monitor serum glucose every 3 months in nondiabetic patients, or as clinically indicated. Monitor serum glucose more frequently in diabetic patients. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue.

Interstitial Lung Disease/Non-infectious Pneumonitis

Risk of interstitial lung disease (ILD)/non-infectious pneumonitis. Based on severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue.

Hemorrhage

Risk of serious and sometimes fatal hemorrhage.

Monitor patients for signs and symptoms of hemorrhage. Based on severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue.

Hypersensitivity Reactions

Possible hypersensitivity reactions.

Hypersensitivity reactions, including anaphylactic, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, reported with oral sirolimus.

Hypersensitivity reactions including anaphylaxis also observed with human albumin.

Monitor patients closely for signs and symptoms of infusion reactions during and following each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion.

Reduce the rate, interrupt infusion, or permanently discontinue based on severity and institute appropriate medical management as needed.

Embryofetal Toxicity

Based on animal studies and the mechanism of action, can cause fetal harm when administered to a pregnant woman. In animal studies, oral sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses. (See Pregnancy under Cautions.)

Male Infertility

Azoospermia or oligospermia may be observed in patients treated with albumin-bound sirolimus.

Immunizations and Risks Associated with Live Vaccines

No studies in conjunction with immunization have been conducted. Immunization during treatment may be ineffective.

Update immunizations according to immunization guidelines prior to initiating treatment, if possible. Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while receiving treatment. The interval between live vaccinations and initiation of albumin-bound sirolimus should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

Risk of Transmission of Infectious Agents with Human Albumin

Contains human albumin, a derivative of human blood. Human albumin carries only a remote risk of transmission of viral diseases because of effective donor screening and product manufacturing processes. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.

No cases of transmission of viral diseases or CJD have ever been associated with albumin.

Specific Populations

Pregnancy

May cause fetal harm based on animal studies and mechanism of action. Limited data on use of sirolimus during pregnancy. Advise pregnant women of the potential risk to a fetus. (See Females and Males of Reproductive Potential under Cautions.)

Lactation

No data exist on presence of albumin-bound sirolimus in human milk or its effects on the breastfed child or on milk production.

Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action.

Advise women not to breastfeed during treatment with albumin-bound sirolimus and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status of females of reproductive potential prior to initiating therapy. Advise females of reproductive potential to use effective contraception during treatment with albumin-bound sirolimus and for 12 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with albumin-bound sirolimus and for 12 weeks after the last dose.

Male and female fertility may be compromised by treatment with albumin-bound sirolimus. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) reported in females receiving oral sirolimus. Azoospermia, which has been reversible upon discontinuation in most cases, reported in males receiving oral sirolimus.

Pediatric Use

Safety and efficacy in pediatric patients not established.

Geriatric Use

Clinical studies of albumin-bound sirolimus did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.

Hepatic Impairment

Not recommended in patients with severe hepatic impairment. Reduce dosage in patients with mild or moderate hepatic impairment.

Common Adverse Effects

Common adverse effects (≥30%): stomatitis, fatigue, rash, infection, nausea, edema, diarrhea, musculoskeletal pain, decreased weight, decreased appetite, cough, vomiting, dysgeusia.

Common grade 3 to 4 laboratory abnormalities (≥6%): decreased lymphocytes, increased glucose, decreased potassium, decreased phosphate, decreased hemoglobin, increased lipase.

General

Pretreatment Screening

• Monitor potassium levels prior to starting albumin-bound sirolimus and implement potassium supplementation as medically indicated.

• Perform routine laboratory testing for assessment of glucose and CBC.

• Update vaccinations according to immunization guidelines prior to initiating albumin-bound sirolimus, if possible.

• Verify pregnancy status of females of reproductive potential prior to initiating albumin-bound sirolimus.

Patient Monitoring

• Perform routine laboratory testing for assessment of potassium, glucose, and CBC.

• Monitor for signs and symptoms of infection, including reactivation of latent viral infections.

• Monitor for signs and symptoms of bleeding due to the risk of hemorrhage.

• Monitor patients closely for signs and symptoms of infusion reactions during and following each albumin-bound sirolimus infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion.

Dispensing and Administration Precautions

• Albumin-bound sirolimus is a hazardous drug. Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

Administration

IV Administration

Administer by IV infusion.

Reconstitution

The lyophilized powder must be reconstituted to an injectable suspension prior to IV infusion.

Using aseptic technique, inject 20 mL of 0.9% sodium chloride injection slowly (over a minimum period of 1 minute) into the vial containing the lyophilized powder. Direct the flow of diluent toward the inside wall of the vial rather than directly on the lyophilized cake to avoid foaming. After addition of diluent, allow vial to sit for a minimum of 5 minutes to ensure thorough wetting of the lyophilized cake/powder. Then, gently swirl and/or invert vial (do not shake) for at least 2 minutes until the cake/powder is completely dissolved; avoid foaming. If foaming or clumping occurs, allow the reconstituted suspension to stand for at least 15 minutes until foaming subsides. Do not use if foaming or clumping is present after 1 hour.

The reconstituted sirolimus suspension has a final concentration of 5 mg/mL.

Transfer the calculated volume of reconstituted albumin-bound sirolimus to an empty PVC or polyolefin infusion bag without further dilution.

Visually inspect reconstituted albumin-bound sirolimus suspension in the infusion bag prior to administration. Discard reconstituted suspension if particulate matter, proteinaceous strands, or discoloration are observed.

Rate of Administration

Administer IV infusion over 30 minutes.

Dosage

Dosage of albumin-bound sirolimus is expressed in terms of sirolimus.

Adults

Perivascular Epithelioid Cell Tumor (PEComa) in Adults

IV

100 mg/m² as an IV infusion on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

Dosage Modifications for Adverse Reactions

Dosage interruption and/or reduction or discontinuance of therapy may be necessary based on severity of adverse reactions. See Table 1 for recommended dose reductions for adverse reactions and Table 2 for recommended dosage modifications/interventions for adverse effects.

Permanently discontinue albumin-bound sirolimus in patients who are unable to tolerate it after 3 dose reductions.

Dosage Modification for Concomitant Use with CYP3A4 and/or P-gp Inhibitors and Inducers

Reduce initial dosage to 56 mg/m² when used concomitantly with a moderate or weak cytochrome P-450 3A4 (CYP3A4) inhibitor.

Avoid concomitant use with strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors and inducers and grapefruit and grapefruit juice.

Special Populations

Hepatic Impairment

Patients with mild (total bilirubin ≤ULN, AST >ULN or total bilirubin >1 to 1.5×ULN, any AST): reduce initial dosage to 75 mg/m².

Patients with moderate hepatic impairment (total bilirubin >1.5 to 3×ULN, any AST): reduce initial dosage to 56 mg/m².

Closely monitor patients with hepatic impairment for increased toxicity. Avoid use in patients with severe hepatic impairment.

Metabolized by CYP isoenzymes, principally CYP3A; substrate of both CYP3A4 and P-gp.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use.

Moderate or Weak CYP3A4 Inhibitors: Use of albumin-bound sirolimus with moderate or weak CYP3A4 inhibitors may result in increased levels of sirolimus. Reduce dosage of albumin-bound sirolimus when used concomitantly with a moderate or weak CYP3A4 inhibitor.

Moderate or Weak CYP3A4 Inducers: Use of albumin-bound sirolimus with moderate or weak CYP3A4 inducers may result in decreased effectiveness.

Drugs Affecting or Affected by Transport Proteins

P-gp Inhibitors or Inducers: Avoid concomitant use of albumin-bound sirolimus with P-gp inhibitors or inducers.

Specific Drugs