EVEROLIMUS (Page 2 of 9)

2.10 Dosage Modifications for Hepatic Impairment

The recommended dosages of everolimus for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6)]:

Table 3: Recommended Dosage Modifications for Patients With Hepatic Impairment

Indication Dose Modification for Everolimus
Breast Cancer and TSC-Associated Renal Angiomyolipoma
  • Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated.
  • Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated.
  • Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily.
TSC-Associated SEGA
  • Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m2 orally once daily.
  • Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)].

Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.

2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors

Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus With a P-gp and Moderate CYP3A4 Inhibitor
Indication Dose Modification for Everolimus
Breast Cancer andTSC-Associated Renal Angiomyolipoma
  • Reduce dose to 2.5 mg once daily.
  • May increase dose to 5 mg once daily if tolerated.
  • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.
TSC-Associated SEGA
  • Reduce the daily dose by 50%.
  • Change to every other day dosing if the reduced dose is lower than the lowest available strength.
  • Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.
  • Assess trough concentrations when initiating and discontinuing the inhibitor [see
Dosage and Administration (2.8)].

2.12 Dosage Modifications for P-gp and CYP3A4 Inducers

Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus With P-gp and Strong CYP3A4 Inducers

Indication Dose Modification for Everolimus
Breast Cancer andTSC-Associated Renal Angiomyolipoma
  • Avoid coadministration where alternatives exist.
  • If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required.
  • Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days.
TSC-Associated SEGA
  • Double the daily dose using increments of 5 mg or less. Multiple increments may be required.
  • Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification.
  • Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8)].
  • Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days.

2.13 Administration and Preparation

  • Administer everolimus at the same time each day.
  • Administer everolimus consistently either with or without food [see Clinical Pharmacology (12.3)].
  • If a dose of everolimus is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, everolimus should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.

Everolimus Tablets

  • Everolimus tablets should be swallowed whole with a glass of water. Do not break or crush tablets.

3 DOSAGE FORMS AND STRENGTHS

Everolimus Tablets

Tablets, White to off white, capsule shaped, flat faced bevelled edge:

• 2.5 mg: debossed with B 2.5 on one side and plain on other side.

• 5 mg: debossed with B 5 on one side and plain on other side.

• 7.5 mg: debossed with B 7.5 on one side and plain on other side.

• 10 mg: debossed with B 10 on one side and plain on other side

4 CONTRAINDICATIONS

Everolimus are contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Non-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.

5.2 Infections

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. The incidence of serious infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4)].

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.

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