VIZIMPRO Film-coated tablet Ref.[7605] Active ingredients: Dacomitinib

Assessment of EGFR mutation status

When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.

Interstitial lung disease (ILD) / Pneumonitis

ILD/pneumonitis, which could be fatal, has been reported in patients receiving Vizimpro (see section 4.8). Patients with a history of ILD have not been studied.

Careful assessment of all patients with an acute onset or unexplained worsening of pulmonary symptoms (e.g., dyspnoea, cough, fever) should be performed to exclude ILD/pneumonitis. Treatment with dacomitinib should be withheld pending investigation of these symptoms. If ILD/pneumonitis is confirmed, dacomitinib should be permanently discontinued and appropriate treatment instituted as necessary (see section 4.2).

Diarrhoea

Diarrhoea, including severe diarrhoea, has been very commonly reported during treatment with Vizimpro (see section 4.8). Diarrhoea may result in dehydration with or without renal impairment, which could be fatal if not adequately treated.

Proactive management of diarrhoea should start at the first sign of diarrhoea especially within the first 2 weeks of starting dacomitinib, including adequate hydration combined with anti-diarrhoeal medicinal products and continued until loose bowel movements cease for 12 hours. Anti-diarrhoeal medicinal products (e.g., loperamide) should be used and, if necessary, escalated to the highest recommended approved dose. Patients may require dosing interruption and/or dose reduction of therapy with dacomitinib. Patients should maintain adequate oral hydration and patients who become dehydrated may require administration of intravenous fluids and electrolytes (see section 4.2).

Skin-related adverse reactions

Rash, erythematous and exfoliative skin conditions have been reported in patients treated with Vizimpro (see section 4.8).

For prevention of dry skin, initiate treatment with moisturizers, and upon development of rash, initiate treatment with topical antibiotics, emollients, and topical steroids. Start oral antibiotics and topical steroids in patients who develop exfoliative skin conditions. Consider adding broad spectrum oral or intravenous antibiotics if any of these conditions worsen to greater than or equal to Grade 2 severity. Rash, erythematous and exfoliative skin conditions may occur or worsen in areas exposed to the sun. Advise patients to use protective clothing and sunscreen before exposure to the sun. Patients may require dosing interruption and/or dose reduction of therapy with dacomitinib (see section 4.2).

Hepatotoxicity and transaminases increased

Transaminases increased (alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased) have been reported during treatment with Vizimpro (see section 4.8). Among NSCLC patients treated with dacomitinib 45 mg daily, there have been isolated reports of hepatotoxicity in 4 (1.6%) patients. Across the dacomitinib program, hepatic failure led to a fatal outcome in 1 patient. Therefore, periodic liver function testing is recommended. In patients who develop severe elevations in transaminases while taking dacomitinib, treatment should be interrupted (see section 4.2).

Medicinal products metabolised by cytochrome P450 (CYP)2D6

Vizimpro may increase exposure (or decrease exposure of active metabolites) of other medicinal products metabolised by CYP2D6. Concomitant use of medicinal products predominantly metabolised by CYP2D6 should be avoided unless such products are considered necessary (see section 4.5).

Other forms of interactions

Concomitant use of proton pump inhibitors (PPIs) with dacomitinib should be avoided (see section 4.5).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains <1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Co-administration of dacomitinib with agents that increase gastric pH

The aqueous solubility of dacomitinib is pH dependent, with low (acidic) pH resulting in higher solubility. Data from a study in 24 healthy subjects indicated that co-administration of a single 45 mg dacomitinib dose with the PPI rabeprazole 40 mg once daily for 7 days decreased dacomitinib C_max, AUC_0-96h (area under the concentration-time curve from time 0 to 96 hours), and AUC_inf (AUC from time 0 to infinity) (n=14) by approximately 51%, 39%, and 29%, respectively, when compared to a single 45 mg dose of dacomitinib administered alone. PPIs should be avoided while receiving treatment with dacomitinib (see section 4.4).

Based on data from observations in 8 patients in Study A7471001, there was no apparent effect of local antacid administration on C_max and AUC_inf of dacomitinib. Based on pooled data in patients, there was no apparent effect of histamine-2 (H2) receptor antagonists on steady-state trough concentration of dacomitinib (geometric mean ratio of 86% (90% CI: 73; 101). Local antacids and H2 receptor antagonists may be used if needed. Dacomitinib should be administered 2 hours before or at least 10 hours after taking H2 receptor antagonists.

Co-administration of dacomitinib and CYP2D6 substrates

Co-administration of single 45 mg oral dose of dacomitinib increased the mean exposure (AUC_last and C_max) of dextromethorphan, a probe CYP2D6 substrate, 855% and 874%, respectively, compared with administration of dextromethorphan alone. These results suggest that dacomitinib may increase exposure of other medicinal products (or decrease exposure to active metabolites) primarily metabolised by CYP2D6. Concomitant use of medicinal products predominantly metabolised by CYP2D6 should be avoided (see section 4.4). If concomitant use of such medicinal products is considered necessary, they should follow their respective labels for dose recommendation regarding co-administration with strong CYP2D6 inhibitors.

Effect of dacomitinib on drug transporters

Based on in vitro data, dacomitinib may have the potential to inhibit the activity of P-glycoprotein (P-gp) (in the gastrointestinal [GI] tract), Breast Cancer Resistance Protein (BCRP) (systemically and GI tract), and organic cation transporter (OCT)1 at clinically relevant concentrations (see section 5.2).

Woman of childbearing potential / Contraception

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Vizimpro. Women of childbearing potential who are receiving this medicinal product should use adequate contraceptive methods during therapy and for at least 17 days (5 half-lives) after completing therapy.

Pregnancy

There are no data on the use of dacomitinib in pregnant women. Studies in animals have shown limited effects on reproductive toxicity (lower maternal body weight gain and food consumption in rats and rabbits, and lower foetal body weight and higher incidence of unossified metatarsals in rats only) (see section 5.3). Based on its mechanism of action, dacomitinib may cause foetal harm when administered to a pregnant woman. Dacomitinib should not be used during pregnancy. Female patients taking dacomitinib during pregnancy or who become pregnant while taking dacomitinib should be apprised of the potential hazard to the foetus.

Breast-feeding

It is not known whether dacomitinib and its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from exposure to dacomitinib, mothers should be advised against breast-feeding while receiving this medicinal product.

Fertility

Fertility studies have not been performed with dacomitinib. Non-clinical safety studies showed reversible epithelial atrophy in the cervix and vagina of rats (see section 5.3).

Vizimpro has minor influence on the ability to drive and use machines. Patients experiencing fatigue or ocular adverse reactions while taking dacomitinib should exercise caution when driving or operating machinery.

Summary of safety profile

The median duration of treatment with Vizimpro across the pooled data set was 66.7 weeks.

The most common (>20%) adverse reactions in patients receiving dacomitinib were diarrhoea (88.6%), rash (79.2%), stomatitis (71.8%), nail disorder (65.5%), dry skin (33.3%), decreased appetite (31.8%), conjunctivitis (24.7%), weight decreased (24.3%), alopecia (23.1%), pruritus (22.4%), transaminases increased (22.0%), and nausea (20.4%).

Serious adverse reactions were reported in 6.7% of patients treated with dacomitinib. The most frequently (≥1%) reported serious adverse reactions in patients receiving dacomitinib were diarrhoea (2.0%), interstitial lung disease (1.2%), rash (1.2%), and decreased appetite (1.2%).

Adverse reactions leading to dose reductions were reported in 52.2% of patients treated with dacomitinib. The most frequently reported (>5%) reasons for dose reductions due to any adverse reactions in patients receiving dacomitinib were rash (32.2%), nail disorder (16.5%), and diarrhoea (7.5%).

Adverse reactions leading to permanent discontinuation were reported in 6.7% of patients treated with dacomitinib. The most common (>0.5%) reasons for permanent discontinuations associated with adverse reactions in patients receiving dacomitinib were: rash (2.4%), interstitial lung disease (2.0%), and diarrhoea (0.8%).

Tabulated list of adverse reactions

Table 3 presents adverse reactions for Vizimpro. Adverse reactions are listed according to system organ class (SOC). Within each SOC, the adverse reactions are ranked by frequency, with the most frequent reactions first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3. Adverse reactions reported in dacomitinib clinical studies (N=255):

Metabolism and nutrition disorders

Very common: Decreased appetite, Hypokalaemia^a

Common: Dehydration

Nervous system disorders

Common: Dysgeusia

Eye disorders

Very common: Conjunctivitis^b

Common: Keratitis

Respiratory, thoracic and mediastinal disorders

Common: Interstitial lung disease^*,c

Gastrointestinal disorders

Very common: Diarrhoea^*, Stomatitis^d, Vomiting, Nausea

Skin and subcutaneous tissue disorders

Very common: Rash^e, Palmar-plantar erythrodysaesthesia, syndrome, Skin fissures, Dry skin^f, Pruritus^g, Nail disorder^h, Alopecia

Common: Skin exfoliationⁱ, Hypertrichosis

General disorders and administration site conditions

Very common: Fatigue, Asthenia

Investigations

Very common: Transaminases increased^j, Weight decreased

Data based on pool of 255 patients who received Vizimpro 45 mg once daily as starting dose for first-line treatment of NSCLC with EGFR-activating mutations across clinical studies.

* Fatal events were reported.
^a Hypokalaemia includes the following preferred terms (PTs): Blood potassium decreased, Hypokalaemia.
^b Conjunctivitis includes the following PTs: Blepharitis, Conjunctivitis, Dry eye, Noninfective conjunctivitis.
^c Interstitial lung disease includes the following PTs: Interstitial lung disease, Pneumonitis.
^d Stomatitis includes the following PTs: Aphthous ulcer, Cheilitis, Dry mouth, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, Stomatitis.
^e Rash (also referred to as Rash and erythematous skin conditions) includes the following PTs: Acne, Dermatitis acneiform, Erythema, Erythema multiforme, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular.
^f Dry skin includes the following PTs: Dry skin, Xerosis.
^g Pruritus includes the following PTs: Pruritus, Rash pruritic.
^h Nail disorder includes the following PTs: Ingrowing nail, Nail bed bleeding, Nail bed inflammation, Nail discolouration, Nail disorder, Nail infection, Nail toxicity, Onychoclasis, Onycholysis, Onychomadesis, Paronychia.
ⁱ Skin exfoliation (also referred to as Exfoliative skin conditions) includes the following PTs: Exfoliative rash, Skin exfoliation.
^j Transaminases increased includes the following PTs: Alanine aminotransferase increased, Aspartate aminotransferase increased, Transaminases increased.

Description of selected adverse reactions

Very common adverse reactions in patients occurring in at least 10% of patients in Study ARCHER 1050 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 4.

Table 4. Very common adverse reactions in Phase 3 Study ARCHER 1050 (N=451):

^a Only adverse reactions with ≥10% incidence in the dacomitinib arm are included.
^b Hypokalaemia includes the following preferred terms (PTs): Blood potassium decreased, Hypokalaemia.
^c Conjunctivitis includes the following PTs: Blepharitis, Conjunctivitis, Dry eye, Noninfective conjunctivitis.
^d 1 fatal event was reported in the dacomitinib arm.
^e Stomatitis includes the following PTs: Aphthous ulcer, Cheilitis, Dry mouth, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, Stomatitis.
^f Rash includes the following PTs: Acne, Dermatitis acneiform, Erythema, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular.
^g Dry skin includes the following PTs: Dry skin, Xerosis.
^h Pruritus includes the following PTs: Pruritus, Rash pruritic.
ⁱ Nail disorder includes the following PTs: Ingrowing nail, Nail discolouration, Nail disorder, Nail infection, Nail toxicity, Onychoclasis, Onycholysis, Onychomadesis, Paronychia.
^j Transaminases increased includes the following PTs: Alanine aminotransferase increased, Aspartate aminotransferase increased, Transaminases increased.

Interstitial lung disease (ILD) / Pneumonitis

ILD/pneumonitis adverse reactions were reported in 2.7% of patients receiving Vizimpro, and Grade ≥3 ILD/pneumonitis adverse reactions were reported in 0.8%, including a fatal event (0.4%) (see section 4.4).

The median time to the first episode of any grade ILD/pneumonitis was 16 weeks and the median time to the worst episode of ILD/pneumonitis was 16 weeks in patients receiving dacomitinib. The median duration of any grade and Grade ≥3 ILD/pneumonitis was 13 weeks and 1.5 weeks, respectively (see section 4.4).

Diarrhoea

Diarrhoea was the most frequently reported adverse reaction in patients receiving Vizimpro (88.6%) and Grade ≥3 diarrhoea adverse reactions were reported in 9.4% of patients. In a clinical study, one patient (0.4%) had a fatal outcome (see section 4.4).

The median time to the first episode of any grade diarrhoea was 1 week and the median time to the worst episode of diarrhoea was 2 weeks in patients receiving dacomitinib. The median duration of any grade and Grade ≥3 diarrhoea was 20 weeks and 1 week, respectively (see section 4.4).

Skin-related adverse reactions

Rash, erythematous and exfoliative skin condition adverse reactions were reported in 79.2% and 5.5%, respectively, of patients receiving Vizimpro. Skin-related adverse reactions were Grades 1 to 3. Grade 3 rash and erythematous skin condition adverse reactions were the most frequently reported Grade 3 adverse reactions (25.5%). Grade 3 exfoliative skin conditions were reported in 0.8% of patients (see section 4.4).

The median time to the first episode of any grade rash and erythematous skin conditions was approximately 2 weeks and the median time to the worst episode of rash and erythematous skin conditions was 7 weeks in patients receiving dacomitinib. The median duration of any grade and Grade ≥3 rash and erythematous skin conditions was 53 weeks and 2 weeks, respectively. The median time to the first episode of any grade exfoliative skin conditions was 6 weeks and the median time to the worst episode of exfoliative skin conditions was 6 weeks. The median duration of any grade and Grade ≥3 exfoliative skin conditions was 10 weeks and approximately 2 weeks, respectively.

Transaminases increased

Transaminases increased (alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased) were reported in 22.0% of patients receiving Vizimpro and were Grades 1 to 3, with the majority Grade 1 (18.4%) (see section 4.4).

The median time to the first episode of any grade of transaminases increased was approximately 12 weeks and the median time to the worst episode of transaminases increased was 12 weeks in patients receiving dacomitinib. The median duration of any grade and Grade ≥3 transaminases increased was 11 weeks and 1 week, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.