Dacomitinib

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. 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.

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.

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.

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.

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

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). 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.

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.

Woman of childbearing potential / Contraception

Women of childbearing potential should be advised to avoid becoming pregnant while receiving dacomitinib. 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.

Fertility

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

Dacomitinib 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 dacomitinib 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%).

List of adverse reactions

The following list presents adverse reactions for dacomitinib. 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.

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 dacomitinib 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 the following table.

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 dacomitinib, and Grade ≥3 ILD/pneumonitis adverse reactions were reported in 0.8%, including a fatal event (0.4%).

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.

Diarrhoea

Diarrhoea was the most frequently reported adverse reaction in patients receiving dacomitinib (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.

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.

Skin-related adverse reactions

Rash, erythematous and exfoliative skin condition adverse reactions were reported in 79.2% and 5.5%, respectively, of patients receiving dacomitinib. 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.

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 dacomitinib and were Grades 1 to 3, with the majority Grade 1 (18.4%).

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.