Everolimus is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.
Contraindications
Everolimus is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions ( 5.3 )] . Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives. ( 4 )
Warnings and precautions
Non-infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. ( 2.9 , 5.1 )
Infections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. (2.9 , 5.2 )
Severe Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. ( 5.3 )
Angioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. ( 5.4 , 7.2 )
Renal Failure: Monitor renal function prior to treatment and periodically thereafter. ( 5.6 )
Risk of Impaired Wound Healing: Withhold for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment after resolution of wound healing complications has not been established. ( 5.7 )
Metabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. ( 2.9 , 5.9 )
Myelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. ( 2.9 , 5.10 )
Risk of Infection or Reduced Immune Response with Vaccination: Avoid live vaccines and close contact with those who have received live vaccines. Complete recommended childhood vaccinations prior to starting treatment. ( 5.11 )
Radiation Sensitization and Radiation Recall: Severe radiation reactions may occur. ( 5.12 , 6.2 )
Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.13 , 8.1 , 8.3 )
5.1Non-infectious Pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with Everolimus in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions ( 6.1 )] .
Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Continue Everolimus without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms.
Imaging appears to overestimate the incidence of clinical pneumonitis. For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue Everolimus based on severity [see Dosage and Administration ( 2.9 )] . Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose.
5.2Infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions ( 6.1 )] . Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP), and viral infections (e.g., reactivation of hepatitis B virus) have occurred.
Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue Everolimus based on severity of infection [see Dosage and Administration ( 2.9 )] .
Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.
5.3Severe Hypersensitivity Reactions
Hypersensitivity reactions to Everolimus have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications ( 4 )] . The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue Everolimus for the development of clinically significant hypersensitivity.
5.4Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors
Patients taking concomitant ACE inhibitors with Everolimus may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking Everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue Everolimus for angioedema.
5.5Stomatitis
Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with Everolimus at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions ( 6.1 )] . Stomatitis most often occurs within the first 8 weeks of treatment. When starting Everolimus, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions ( 6.1 )] .
If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed.
5.6Renal Failure Cases
of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking Everolimus. Elevations of serum creatinine and proteinuria have been reported in patients taking Everolimus [see Adverse Reactions ( 6.1 )] . The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively.
Monitor renal function prior to starting Everolimus and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.
5.7Risk of Impaired Wound Healing
Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, Everolimus has the potential to adversely affect wound healing. Withhold Everolimus for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established.
5.9Metabolic Disorders
Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking Everolimus at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions ( 6.1 )] . In non-diabetic patients, monitor fasting serum glucose prior to starting Everolimus and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated.
Monitor lipid profile prior to starting Eve
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P-gp and moderate CYP3A4 Inhibitors: Reduce the dose as recommended. ( 2.11 , 7.1 )
P-gp and strong CYP3A4 Inducers: Increase the dose as recommended. ( 2.12 , 7.1 )
7.1Effect of Other Drugs on Everolimus Inhibitors Avoid
the concomitant use of P-gp and strong CYP3A4 inhibitors [see Dosage and Administration ( 2.11 ), Clinical Pharmacology ( 12.3 )] . Reduce the dose for patients taking Everolimus with a P-gp and moderate CYP3A4 inhibitor as recommended [see Dosage and Administration ( 2.11 ), Clinical Pharmacology ( 12.3 )] . Inducers Increase the dose for patients taking Everolimus with a P-gp and strong CYP3A4 inducer as recommended [see Dosage and Administration ( 2.12 ), Clinical Pharmacology ( 12.3 )] .
7.2Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors
Patients taking concomitant ACE inhibitors with Everolimus may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with Everolimus [see Warnings and Precautions ( 5.4 )] .
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on animal studies and the mechanism of action [see Clinical Pharmacology ( 12.1 )] , Everolimus can cause fetal harm when administered to a pregnant woman. There are limited case reports of Everolimus use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of Everolimus 10 mg orally once daily [see Data].
Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively. Data Animal Data: In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development.
These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥0.1 mg/kg (0.6 mg/m 2 ) with resulting exposures of approximately 4% of the human exposure at the recommended dose of Everolimus 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m 2 ).
The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of ≥0.1 mg/kg (0.6 mg/m 2 ), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing).
There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.
Adverse reactions
The following serious adverse reactions are described elsewhere in the labeling:
Metabolic Disorders [see Warnings and Precautions ( 5.9 )] .
Myelosuppression [see Warnings and Precautions ( 5.10 )] .
Radiation Sensitization and Radiation Recall [see Warnings and Precautions ( 6.2 )].
RCC: Most common adverse reactions (incidence ≥30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. ( 6.1 )
TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The data described below reflect exposure to Everolimus (n=274) and placebo (n=137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib.
The median age of patients was 61 years (27 to 85 years), 88% were white, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving Everolimus. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3 to 4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia.
The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3 to 4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Everolimus arm.
The rate of adverse reactions resulting in permanent discontinuation was 14% for the Everolimus group. The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during Everolimus treatment were for infections, anemia, and stomatitis.
Adverse reactions reported with an incidence of ≥ 10% for patients receiving Everolimus vs. placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13. Table 12: Adverse Reactions Reported in ≥ 10% of Patients with RCC and at a Higher Rate in the Everolimus Arm than in the Placebo Arm in RECORD-1 Everolimus N = 274 Placebo N = 137 All Grades Grades 3-4 All Grades Grades 3-4 % % % % Gastrointestinal Stomatitis Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. 44 4 8 0 Diarrhea 30 2 No Grade 4 adverse reactions were reported. 7 0 Nausea 26 2 19 0 Vomiting 20 2 12 0 Infections Includes all reported infections including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. 37 10 18 2 General Asthenia 33 4 23 4 Fatigue 31 6 27 4 Edema peripheral 25 <1 8 <1 Pyrexia 20 <1 9 0 Mucosal inflammation 19 2 1 0 Respiratory, Thoracic and Mediastinal Cough 30 <1 16 0 Dyspnea 24 8 15 3 Epistaxis 18 0 0 0 Pneumonitis Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. 14 4 4 0 0 Skin and Subcutaneous Tissue Rash 29 1 7 0 Pruritus 14 < 1 7 0 Dry skin 13 < 1 5 0 Metabolism and Nutrition Anorexia 25 2 14 <1 Nervous System Headache 19 1 9 <1 Dysgeusia 10 0 2 0 Musculoskeletal and Connective Tissue Pain in extremity 10 1 7 0 Grading according to NCI CTCAE Version 3.0.
Other notable adverse reactions occurring more frequently with Everolimus than with placebo, but with an incidence of <10% include: Gastrointestinal : Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General : Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, Thoracic and Mediastinal : Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and Subcutaneous Tissue : Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (<1%) Metabolism and Nutrition : Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric : Insomnia (9%) Nervous System : Dizziness (7%), paresthesia (5%) Ocular: Eyelid edema (4%), conjunctivitis (2%) Vascular : Hypertension (4%), deep vein thrombosis (<1%) Renal and Urinary : Renal failure (3%) Cardiac : Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and Connective Tissue : Jaw pain (3%) Hematologic : Hemorrhage (3%) Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the Everolimus Arm Than the Placebo Arm in RECORD-1 Laboratory Parameter Everolimus N = 274 Placebo N = 137 All Grades Grade 3-4 All Grades Grade 3-4 % % % % Hematology Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency.
Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) of Everolimus in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The median age of patients was 31 years (18 to 61 years), 89% were white, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving Everolimus.
The most common adverse reaction reported for Everolimus (incidence ≥ 30%) was stomatitis. The most common Grade 3 to 4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3 to 4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the Everolimus-treated patients.
Adverse reactions leading to permanent discontinuation in the Everolimus arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of Everolimus-treated patients. The most common adverse reaction leading to Everolimus dose adjustment was stomatitis. Adverse reactions reported with an incid
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
EVEROLIMUS 2.5MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Everolimus
Drug class
Mammalian target of rapamycin (mTOR) kinase inhibitors
