Medicinal Products

AFINITOR 10 mg

Generic drug of the therapeutic class: Oncology and Hematology
active ingredients: Everolimus
laboratory: Novartis Europharm Ltd

Compressed
Box of 3 blister packs of 10
All forms

Indication

Advanced breast cancer with positive hormone receptors

Afinitor is indicated for the treatment of advanced hormone receptor-positive breast cancer, HER2 / neu-negative, in combination with exemestane, in postmenopausal women without symptomatic visceral involvement following recurrence or progression of the disease and previously treated with a non-inhibitory inhibitor. -stheroidal aromatase.

Neuroendocrine tumors of pancreatic origin

Afinitor is indicated for the treatment of unresectable or metastatic pancreatic neuroendocrine tumors that are well or moderately differentiated with progression of the disease in adults.

Kidney cancer

Afinitor is indicated for the treatment of advanced kidney cancer in patients who have progressed under or after targeted anti-VEGF therapy.

Dosage AFINITOR 10 mg Tablet Box of 3 blister packs of 10

Afinitor treatment should be started and followed by a doctor experienced in cancer treatments.

Dosage

For different dosages Afinitor is available in 2.5 mg, 5 mg and 10 mg tablets.

The recommended dose of everolimus is 10 mg once daily. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs. If a dose is missed, the patient should not take an extra dose, but take the next prescribed dose as usual. Dosage Adjustment for Adverse Events Management of serious and / or poorly tolerated adverse reactions suspected to be treatment-related may require dose reduction and / or temporary discontinuation of Afinitor therapy. For Grade 1 adverse events, dose adjustment is not usually necessary. If it is necessary to reduce the dosage, the recommended dose is 5 mg per day and should not be less than 5 mg per day.

Table 1 summarizes the recommendations for dose adjustment for specific adverse events (see also Warnings and Precautions ).

Table 1 Recommendations for Dosage Adjustment of Afinitor

Undesirable effect

Severity 1

Dosage adjustment of Afinitor

Noninfectious pneumonitis

Grade 2

Consider interruption of treatment until improvement

symptoms at Grade ≤ 1.

Re-introduce the 5 mg daily treatment.

Stop treatment in the absence of recovery in a

4 weeks delay.

Grade 3

Discontinue treatment until symptom resolution at Grade ≤ 1.

Consider resuming 5 mg daily. If Grade 3 toxicity reappears, consider stopping treatment.

Grade 4

Stop the treatment.

stomatitis

Grade 2

Interrupt the treatment temporarily until

recovery to Grade ≤ 1.

Re-introduce the treatment at the same dose.

In case of recurrence of Grade 2 stomatitis, discontinue

treatment until recovery to Grade ≤ 1.

Re-introduce the 5 mg daily treatment.

Grade 3

Discontinue treatment temporarily until recovery to Grade ≤ 1. Re-introduce treatment at 5 mg daily.

Grade 4

Stop the treatment.

Other toxicities

no

hematologic (except metabolic events)

Grade 2

If the toxicity is acceptable, no adaptation of the

dosage is necessary.

If the toxicity comes unacceptable, interrupt

temporarily treatment until recovery at a

Grade ≤ 1. Re-introduce the treatment at the same dose.

If Grade 2 toxicity recurs, discontinue treatment until recovery to Grade ≤ 1.

Re-introduce the 5 mg daily treatment.

Grade 3

Temporarily abort treatment until recovery to Grade ≤ 1.

Consider re-introducing the 5 mg daily regimen. Yes

Grade 3 toxicity reappears, consider stopping treatment.

Grade 4

Stop the treatment.

Metabolic events (by

example

hyperglycemia, dyslipidemia)

Grade 2

No dosage adjustment is necessary.

Grade 3

Abort the treatment temporarily.

Re-introduce the 5 mg daily treatment.

Grade 4

Stop the treatment.

thrombocytopenia

Grade 2

(<75,

≥ 50x10 9 / l)

Interrupt the treatment temporarily until

recovery to Grade ≤ 1 (≥ 75x10 9 / l). Re-introduce the

treatment at the same dose.

Grade 3 & 4

(<50x10 9 / l)

Interrupt the treatment temporarily until recovery to Grade ≤ 1 (≥ 75x10 9 / l). Re-introduce the

treatment at 5 mg daily.

neutropenia

Grade 2

(≥ 1x10 9 / l)

No dosage adjustment is necessary.

Grade 3

(<1, ≥ 0.5x10 9 / l)

Interrupt the treatment temporarily until

r establishment at Grade ≤ 2 (≥ 1x10 9 / l). Re-introduce the treatment at the same dose.

Grade 4

(<0.5x10 9 / l)

Interrupt the treatment temporarily until

Recovery to Grade ≤ 2 (≥ 1x10 9 / l) Re - introduce treatment to 5 mg daily.

neutropenia

febrile

Grade 3

Discontinue treatment temporarily until recovery to Grade ≤ 2 (≥ 1, 25x10 9 / l) and no fever.

Re-introduce the 5 mg daily treatment.

Grade 4

Stop the treatment.

1 Grades evaluated according to the international classification scale CTCAE (Common

Terminology Criteria for Adverse Events) v3.0 of the National Cancer Institute (NCI)

Special population
Elderly patients (≥ 65 years old)

No dosage adjustment is necessary (see section 5.2 ).

Renal failure

No dosage adjustment is necessary (see section 5.2 ).

Hepatic insufficiency

• Mild hepatic impairment (Child-Pugh Class A) - the recommended daily dose is 7.5 mg.

• Moderate hepatic insufficiency (Child-Pugh class B) - the recommended daily dose is 5 mg.

• Severe hepatic insufficiency (Child-Pugh class C) - Afinitor is only recommended if the expected benefit outweighs the risk. In this case, the daily dose should not exceed 2.5 mg.

Dosage adjustment should be performed if the patient's hepatic function (Child-Pugh) changes during treatment (see also sections Warnings and Precautions for Use and Pharmacokinetic Properties ).

Pediatric population

The safety and effectiveness of Afinitor in children aged 0 to 18 years have not been established. No data available.

Administration mode

Afinitor should be taken orally once a day at the same time each day, with or without food steadily (see section Pharmacokinetic properties ). Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.

Against indications

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed under Composition .

Adverse effects Afinitor

Tolerance Profile Summary

The safety profile is derived from pooled data from 2, 406 Afinitor-treated patients in eight clinical studies, including four randomized, double-blind, placebo-controlled phase III studies and four phase II studies, based on approved indications. The most common adverse events (incidence ≥ 1/10) from pooled safety data were (in descending order): stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemias, dysgeusia, pneumopathies, decreased weight, peripheral edema, asthenia, pruritus, epistaxis, hyperglycemia, hypercholesterolemia, headache and vomiting. The most common adverse reactions of Grades 3-4 (frequency ≥ 1/100 to <1/10) were: stomatitis, anemia, hyperglycemia, fatigue, infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, proteinuria, lymphopenia, hypophosphatemia, rash and hypertension. Grades follow the CTCAE version 3.0 classification.

List of adverse reactions in tabular form

Table 3 shows the adverse event frequency categories reported in the pooled analyzes taken into account for pooled tolerance. Adverse effects are presented according to MedDRA organ classes and frequency categories. Frequency categories are defined according to the following convention: very common (≥ 1/10); frequent (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10 000, <1/1000); very rare (<1 / 10, 000), not known (can not be stimulated based on available data). Within each frequency group, adverse effects should be presented in order of decreasing severity.

Table 3 Adverse Reactions Reported in Clinical Studies

Infections and infestations

Very common

Infections a, *

Blood and lymphatic system disorders

Very common

Anemia

Frequent

Thrombocytopenia, neutropenia, leukopenia, lymphopenia

Rare

pancytopenia

Rare

Pure red cell aplasia

Immune system disorders

Rare

hypersensitivity

Metabolism and nutrition disorders

Very common

Decreased appetite, hyperglycemia, hypercholesterolemia

Frequent

Hypertriglyceridaemia, hypophosphatemia, diabetes mellitus, hyperlipidemia, hypokalemia, dehydration, hypocalcemia

Psychiatric disorders

Frequent

Insomnia

Nervous system disorders

Very common

Dysgeusia, headache

Rare

ageusia

Eye disorders

Frequent

Edema of the eyelid

Rare

Conjunctivitis

Heart conditions

Rare

Congestive heart failure

Vascular disorders

Frequent

Hypertension, hemorrhage b

Rare

Flushing vasomotor, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Very common

Pneumopathy c, epistaxis

Frequent

Cough dyspnea

Rare

Hemoptysis, pulmonary embolism

Rare

Acute Respiratory Distress Syndrome

Gastrointestinal disorders

Very common

Stomatitis, diarrhea, nausea, vomiting

Frequent

Oral dryness, abdominal pain, mucositis, oral pain, dyspepsia, dysphagia

Hepatobiliary disorders

Frequent

Increased alanine aminotransferase, increased aspartate aminotransferase

Affections of the skin and subcutaneous tissue

Very common

Rash, itching

Frequent

Skin dryness, nail alteration, mild alopecia, acne, erythema, onychoclasia, hand-foot syndrome, exfoliation, skin lesion

Rare

Angioedema

Musculoskeletal and systemic disorders

Frequent

arthralgia

Renal and urinary disorders

Frequent

Proteinuria *, increased creatinine, renal failure *

Rare

Increased diurnal urination, acute renal failure *

Disorders of reproductive organs and breast

Rare

Irregular menstruation

Rare

Amenorrhea

General disorders and administration site conditions

Very common

Fatigue, peripheral edema, asthenia

Frequent

pyrexia

Rare

Non-cardiac chest pain

Rare

Alteration of wound healing

investigations

Very common

Weightloss

* See also the sub-section "Description of certain adverse effects"

a Includes all effects of the organ class "infections and infestations" including (frequent) pneumonia and (infrequent) herpes zoster, sepsis and isolated cases of opportunistic infections [eg, aspergillosis, candidiasis and hepatitis B (see also section 4.4)]

b Includes different haemorrhagic events not listed individually

c Includes (frequent) pulmonary interstitial pneumonitis, pulmonary infiltration and (rare)

pulmonary alveolar hemorrhage, pulmonary toxicity and alveolitis

d Includes (very common) stomatitis, (common) canker sores, oral ulcer and tongue and (uncommon) glossod ynie, glossitis

Description of some adverse effects

In cases reported during clinical studies and spontaneously after marketing, everolimus has been associated with severe cases of reactivation of hepatitis B, including a case of fatal outcome. The reactivation of infections is an expected effect during the immunosuppression phases.

In clinical studies and pharmacovigilance reports for spontaneous notification, everolimus has been associated with reports of renal failure (including fatal outcomes) and proteinuria. Monitoring of renal function is recommended (see section Warnings and precautions for use ).

In cases reported during clinical studies and spontaneously after marketing, everolimus has been associated with amenorrhea (secondary amenorrhea and other menstrual irregularities).

The elderly

When pooling safety data, 36% of Afinitor-treated patients were 65 years of age or older. The number of patients with an adverse event that led to discontinuation was higher in patients 65 years and older (19% vs. 12%). The most common adverse events leading to discontinuation were pneumopathies, stomatitis, fatigue and dyspnoea.

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals report any suspected adverse reactions via the national reporting system - see Annex V.

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