Afinitor5 mg

Afinitor is an oral mTOR (mammalian target of rapamycin) inhibitor with two broad categories of approved use: certain cancers/tumor conditions, and prevention of organ transplant rejection (in a lower-dose formulation used with other immunosuppressants).

Established / FDA-approved oncology and tumor indications

• Hormone receptor-positive, HER2-negative advanced breast cancer in postmenopausal women, in combination with exemestane, after failure of letrozole or anastrozole.
• Advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
• Progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal, lung, or pancreatic origin that are unresectable, locally advanced, or metastatic.
• Renal angiomyolipoma associated with tuberous sclerosis complex (TSC), not requiring immediate surgery.
• Subependymal giant cell astrocytoma (SEGA) associated with TSC that requires therapeutic intervention but is not amenable to curative surgical resection (a dispersible tablet formulation is used in younger children).
• Adjunctive treatment of TSC-associated partial-onset seizures, in patients 2 years of age and older.

Established use requiring combination therapy (transplant rejection prophylaxis)

• Prophylaxis of organ rejection in adult kidney transplant recipients at low-to-moderate immunologic risk, used in combination with reduced-dose cyclosporine, basiliximab induction, and corticosteroids.
• Prophylaxis of organ rejection in adult liver transplant recipients, used with reduced-dose tacrolimus and corticosteroids (not started within the first month after liver transplant because of an increased risk of hepatic artery thrombosis).
• Prophylaxis of organ rejection in adult heart transplant recipients, used with reduced-dose cyclosporine and corticosteroids.

Note: the transplant-rejection indication uses a different, lower-dose product/trough-target than the oncology indications; the two uses are not interchangeable.

Each tablet or dispersible tablet contains Everolimus as the active ingredient. Common oncology-indication strengths include 2.5 mg, 5 mg, and 10 mg tablets; the dispersible tablet form is available in lower strengths (e.g., 2 mg, 3 mg, 5 mg) for weight/body-surface-area-based dosing. A separate lower-strength tablet formulation is used for the transplant-rejection indication (e.g., 0.25 mg, 0.5 mg, 0.75 mg). Inactive ingredients vary by manufacturer and formulation (typically include butylated hydroxytoluene, magnesium stearate, lactose, hypromellose, crospovidone, and lactose monohydrate).

Afinitor is a semi-synthetic derivative of sirolimus (rapamycin) that acts as an inhibitor of the mTOR (mammalian target of rapamycin) signaling pathway, an intracellular pathway that regulates cell growth, proliferation, metabolism, and angiogenesis. By blocking mTOR, Afinitor reduces tumor cell proliferation and blood vessel growth in tumors, and separately dampens T-lymphocyte activation and proliferation, which is the basis for its use in preventing transplant rejection. Afinitor is taken orally, once daily, and is available as standard tablets and as dispersible tablets that can be mixed with water for patients who cannot swallow tablets whole.

Afinitor belongs to the class of mTOR (mammalian target of rapamycin) inhibitors, also referred to as rapamycin analogs ("rapalogs"). Depending on indication, it functions as an antineoplastic (anticancer) agent or as an immunosuppressant used in transplant medicine.

Everolimus binds to the intracellular protein FKBP-12, and the resulting complex inhibits the activity of mTOR complex 1 (mTORC1), a central regulator of protein synthesis, cell growth, and metabolism that is often dysregulated in cancer. Inhibition of mTORC1 by Everolimus reduces the activity of downstream effectors (S6 ribosomal protein kinase and eukaryotic initiation factor 4E-binding protein), leading to decreased translation of proteins involved in cell cycle progression, glycolysis, and angiogenesis (partly via reduced hypoxia-inducible factor and vascular endothelial growth factor activity). This produces anti-proliferative and anti-angiogenic effects in susceptible tumors. In the immune system, mTOR inhibition by Everolimus blocks interleukin-driven proliferation of T-lymphocytes and B-lymphocytes, reducing the immune response responsible for graft rejection.

Pharmacokinetics: Everolimus is absorbed orally with peak plasma concentration reached in 1-2 hours; absorption is reduced by high-fat meals. It is extensively metabolized by the hepatic CYP3A4 enzyme (and to a lesser extent CYP3A5 and P-glycoprotein transporter), meaning drug interactions with CYP3A4/P-gp modulators are clinically important. The elimination half-life is approximately 30 hours, supporting once-daily dosing, and it is eliminated predominantly via feces with a smaller renal fraction.

Afinitor is taken by mouth once daily, at the same time each day, consistently with or without food. Standard tablets should be swallowed whole with water and not chewed or crushed. Dispersible tablets should not be swallowed whole; they must be dispersed in a small amount of water immediately before use, as instructed by the pharmacist. Missed doses should generally be taken as soon as remembered on the same day but not doubled up; consult the physician if a dose is missed by transplant patients since blood-level monitoring may be affected.

Afinitor is a substrate of the CYP3A4 enzyme and the P-glycoprotein (P-gp) transporter, so drugs that affect these pathways can significantly raise or lower Afinitor blood levels.

• Strong CYP3A4/P-gp inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir, nefazodone): substantially increase Afinitor exposure and toxicity risk; concurrent use should generally be avoided.
• Moderate CYP3A4/P-gp inhibitors (e.g., erythromycin, fluconazole, verapamil, diltiazem, certain grapefruit juice products): increase Afinitor exposure; dose reduction of Afinitor is generally required with close monitoring.
• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, phenobarbital, St. John's Wort): significantly reduce Afinitor levels and may cause loss of efficacy; a dose increase of Afinitor may be needed if coadministration cannot be avoided.
• ACE inhibitors (e.g., enalapril, ramipril): concurrent use with Afinitor has been associated with an increased risk of angioedema; monitor closely.
• Live vaccines and close contacts of live-vaccine recipients: should be avoided during treatment with Afinitor because of its immunosuppressive effect.
• Calcineurin inhibitors (cyclosporine, tacrolimus) used together in transplant regimens: can increase risk of nephrotoxicity and hyperlipidemia; doses of both agents are individually adjusted and monitored by the transplant team.

Adverse effects of Afinitor vary somewhat by indication but commonly include:

• Very common: mouth sores/stomatitis, fatigue, diarrhea, nausea, decreased appetite, rash, peripheral edema, headache, cough, fever.
• Metabolic: hyperglycemia, hyperlipidemia (elevated cholesterol/triglycerides), which may require monitoring and treatment.
• Hematologic: anemia, low white blood cell counts (increasing infection risk), low platelet counts.
• Respiratory: non-infectious pneumonitis (cough, shortness of breath, may require dose interruption or corticosteroids) — see Precautions and Warnings.
• Infections: increased susceptibility to bacterial, fungal, viral, and opportunistic infections due to immunosuppressive effect — see Precautions and Warnings.
• Renal: increased creatinine, proteinuria.
• Skin/mucosal: rash, dry skin, nail disorders, acneiform dermatitis.
• Less common but serious: angioedema, impaired wound healing, and (in transplant patients specifically) renal artery/vein thrombosis risk in the early post-transplant period — see Precautions and Warnings.

Report any new or worsening symptoms, especially breathing difficulty, unusual bleeding, signs of infection, or swelling of the face/throat, to a physician promptly.

Pregnancy: Based on animal data and its mechanism of action, Afinitor can cause fetal harm and is not recommended during pregnancy. Women of reproductive potential should use effective contraception during treatment with Afinitor and for a period after the last dose (generally around 8 weeks), as advised by the physician. Afinitor should be used in pregnancy only if there is no safer alternative and a physician determines that the potential benefit justifies the potential risk to the fetus.

Lactation: It is not known whether Afinitor passes into human breast milk, but because of the potential for serious adverse reactions in a breastfed infant, breastfeeding is generally not recommended during treatment with Afinitor and for a period after the last dose. Discuss infant feeding plans with the treating physician.

Afinitor requires close medical supervision because of several serious risks:

• Increased risk of infections: Afinitor has immunosuppressive properties and can increase susceptibility to bacterial, fungal, viral, and opportunistic infections (including reactivation of latent infections such as hepatitis B or tuberculosis); monitor for signs of infection and treat promptly.
• Non-infectious pneumonitis: Cases of interstitial lung disease/pneumonitis have occurred; new or worsening respiratory symptoms should be evaluated promptly and may require dose interruption, reduction, discontinuation, or corticosteroid treatment.
• Renal artery/vein thrombosis and graft loss (transplant use): An increased risk of renal artery and vein thrombosis, usually within the first 30 days after kidney transplantation, has been reported, which can result in graft loss; appropriate perioperative management is required.
• Impaired wound healing: Afinitor can impair wound healing and increase the risk of wound-related complications, particularly around the time of surgery; the physician may temporarily withhold treatment before and after surgical procedures.
• Hyperglycemia and hyperlipidemia: Regular monitoring of blood glucose and lipid profile is recommended, particularly in patients with pre-existing diabetes or dyslipidemia.
• Angioedema: Risk is increased with concurrent ACE inhibitor use; seek urgent care for facial, lip, tongue, or throat swelling.
• Hepatic impairment: Dose adjustment is required (see Dosage and Administration); liver function should be monitored.
• Live vaccines: Avoid live vaccines and close contact with recently vaccinated individuals during treatment due to immunosuppression.
• Hepatic artery thrombosis (liver transplant): Afinitor is not started within the first month after liver transplantation due to an increased risk of hepatic artery thrombosis, including graft loss and death.

Regular laboratory monitoring (renal function, liver function, blood counts, glucose, lipids, and, in transplant patients, drug trough levels) is required throughout treatment with Afinitor.

Limited clinical experience with Afinitor overdose exists. In case of a suspected overdose, seek immediate medical attention or contact emergency services/a poison control center. General supportive measures should be provided by medical professionals as needed; there is no specific antidote for Afinitor overdose. Do not attempt to manage a suspected overdose at home.

Store at room temperature, below 30°C, away from light and moisture, in the original blister/container. Keep out of reach and sight of children.

Renal impairment: No specific dose adjustment based on renal function alone is generally required for the oncology indications, but renal function should be monitored, especially in transplant patients where nephrotoxic calcineurin inhibitors are also used.

Hepatic impairment: Dose reduction is required based on Child-Pugh classification (see Dosage and Administration).

Elderly: No overall differences in safety/efficacy have been established compared with younger adults, but elderly patients may be more susceptible to certain adverse effects (e.g., infections, fatigue); use with appropriate monitoring.

Pediatric use: Established for TSC-associated SEGA (age 1 year and older) and TSC-associated partial-onset seizures (age 2 years and older) using body-surface-area-based dosing and therapeutic drug monitoring; safety and efficacy for other oncology indications and for organ transplant rejection prophylaxis have not been established in children.

Immunocompromised patients: Use with particular caution given the additive immunosuppressive effect and infection risk.

For oncology indications, Afinitor is generally continued as long as clinical benefit is observed and toxicity remains acceptable, as determined by the treating oncologist through periodic response assessment. For TSC-associated SEGA and seizures, treatment is typically long-term with periodic reassessment and trough-level monitoring. For organ transplant rejection prophylaxis, Afinitor is generally continued long-term as part of the maintenance immunosuppressive regimen, under the transplant physician's supervision. Do not stop or change the duration of treatment without medical advice.

mTOR (mammalian target of rapamycin) inhibitor; antineoplastic agent; immunosuppressant (rapamycin analog/"rapalog").

Everolimus binds intracellular FKBP-12 and inhibits mTOR complex 1 (mTORC1), suppressing downstream signaling (S6K1, 4E-BP1) that drives cell growth, proliferation, metabolism, and angiogenesis in tumor cells, and suppressing cytokine-driven T-cell and B-cell proliferation in the immune system, which underlies its antitumor and immunosuppressant/anti-rejection effects respectively.

Afinitor is approved in pediatric patients for TSC-associated subependymal giant cell astrocytoma (SEGA) requiring therapeutic intervention (age 1 year and older) and for adjunctive treatment of TSC-associated partial-onset seizures (age 2 years and older), using weight/body-surface-area-based dosing with therapeutic drug monitoring to a target trough concentration. Safety and efficacy of Afinitor for breast cancer, renal cell carcinoma, neuroendocrine tumors, and organ transplant rejection prophylaxis have not been established in pediatric patients outside of these specific approved settings, and use in children for other indications should only occur under specialist supervision.