Dexilant 30 mg & 60 mg Modified-release capsules, hard

4.1 Therapeutic indications

DEXILANT is indicated in adults and in adolescents aged 12 to 17 years for the following:

• Treatment of erosive reflux oesophagitis
• Maintenance of healed erosive reflux oesophagitis and maintenance of relief of heartburn for up to 6 months in adults and up to 4 months in adolescents
• Short-term treatment of heartburn and acid regurgitation associated with symptomatic non-erosive gastro-oesophageal reflux disease (GORD)

4.2 Posology and method of administration

Posology

- Treatment of erosive reflux oesophagitis

Adults and adolescents aged 12 to 17 years

- The recommended dose is 60 mg once daily for 4 weeks. In patients not fully healed within this time, the treatment may be continued at the same dose for another 4 weeks.

Maintenance of healed erosive reflux oesophagitis and maintenance of relief of heartburn

Adults

- The recommended dose is 30 mg once daily for up to 6 months in patients where prolonged acid suppression is needed.

Adolescents aged 12 to 17 years

- The recommended dose is 30 mg once daily for up to 4 months in patients where prolonged suppression is needed. Current evidence does not support a specific treatment period time. A decision should be taken by the clinician on a case by case basis.

Symptomatic non-erosive gastro-oesophageal reflux disease (GORD)

Adults and adolescents aged 12 to 17 years

- The recommended dose is 30 mg once daily for up to 4 weeks.

Special populations

Elderly

Due to reduced clearance of DEXILANT in the elderly an adjustment of dose may be necessary based on individual requirements. A daily dose of 60 mg should not be exceeded in the elderly unless there are compelling clinical indications (see section 5.2).

Renal impairment

No dosage adjustment is necessary for patients with renal impairment (see section 5.2).

Hepatic impairment

No dosage adjustment is necessary for patients with mild hepatic impairment. Patients with moderate hepatic impairment should be kept under regular supervision and a maximum daily dose of 30 mg should be considered. No studies have been conducted in patients with severe hepatic impairment (see sections 4.4 and 5.2), the use of DEXILANT is not recommended for these patients.

Paediatric population

Adolescents aged 12 to 17 years

Treatment of erosive reflux oesophagitis

The posology of DEXILANT in adolescents aged 12 to 17 years is the same as in adults.

Maintenance of healed erosive reflux oesophagitis and maintenance of relief of heartburn

The dose of DEXILANT in adolescents aged 12 to 17 years is the same as in adults.

Symptomatic non-erosive gastro-oesophageal reflux disease (GORD)

The posology of DEXILANT in adolescents aged 12 to 17 years is the same as in adults.

Children under 12 years of age

The safety and efficacy of DEXILANT in children under 12 years of age have not been established. No data are available.

Method of administration

Oral use. Capsules should be swallowed whole with liquid. They can be taken with or without food (see section 5.2). Capsules may also be opened, and granules mixed with one tablespoon apple sauce for administration. After preparing the mixture, the medicinal product should be administered immediately. Granules should not be chewed.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

PPIu2019s, including DEXILANT are contraindicated with rilpivirine-containing products (see section 4.5)

Hypersensitivity reactions may include acute tubulointerstitial nephritis. See section 4.4

4.4 Special warnings and precautions for use

The possibility of malignant gastric tumour should be excluded when using DEXILANT because DEXILANT can mask the symptoms and delay the diagnosis.

Acute tubulointerstitial nephritis (see section 4.3)

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs including DEXILANT. Acute tubulointerstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Acute tubulointerstitial nephritis may lead to chronic renal failure.

Healthcare professionals should frequently monitor renal function and check the urine for haematuria and/or proteinuria in patients on treatment with PPIs such as DEXILANT.

Discontinue DEXILANT if acute tubulointerstitial nephritis develops.

Co-administration of DEXILANT is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH, such as atazanavir or nelfinavir, due to significant reduction in their bioavailability (see section 4.5).

DEXILANT should be used with caution in patients with moderate hepatic dysfunction. DEXILANT is not recommended for patients with severe hepatic impairment (see sections 4.2 and 5.2).

DEXILANT, Treatment with dexlansoprazole may lead to slightly increased risk of gastrointestinal infections such as and Clostridium difficile.

Because of limited safety data for patients on treatment for longer than 6 months regular review of the treatment and a thorough risk/benefit assessment should regularly be performed in these patients.

Severe hypomagnesaemia has been reported in patients treated with PPIs like DEXILANT for at least three months, in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, delirium, convulsions, dizziness and ventricular arrhythmia can occur, but they may begin insidiously and be overlooked. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see section 4.8). In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Influence on Vitamin B-12 Absorption

DEXILANT, may reduce the absorption of vitamin B-12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B-12 absorption on long-term therapy or if respective clinical symptoms are observed.

DEXILANT may cause colitis. Cases of colitis have been reported infrequently for DEXILANT therefore in the case of severe or persistent diarrhoea discontinue DEXILANT.

DEXILANT, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Patients treated with DEXILANT for more than one year should take Vitamin D and calcium supplementation.

When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high dose methotrexate administration, a temporary withdrawal of DEXILANT may need to be considered.

As DEXILANT contains sucrose, patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and erythema multiforme have been reported in association with the use of PPIs (see section 4.8). Discontinue DEXILANT at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, DEXILANT should be discontinued. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, DEXILANT treatment should be stopped for at least 5 days before CgA measurements (see section 5.1). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Effects of other medicinal products on DEXILANT

CYP2C19 and CYP3A4 have been shown to be involved in the metabolism of DEXILANT

Medicinal products which inhibit CYP2C19

Inhibitors of CYP2C19 (such as fluvoxamine) would likely increase the systemic exposure of DEXILANT

Medicinal products which induce CYP2C19 and CYP3A4

Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St Johnu2019s wort (Hypericum perforatum) may reduce the plasma concentrations of DEXILANT.

Others

Sucralfate/Antacids may decrease the bioavailability of DEXILANT. Therefore, DEXILANT should be taken at least 1 hour after taking these drugs.

Effects of DEXILANT on other medicinal products

Medicinal products with pH dependent absorption

DEXILANT may interfere with the absorption of medicinal products where gastric pH is critical to bioavailability HIV protease inhibitors

Co-administration of DEXILANT is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH, such as atazanavir or nelfinavir- due to significant reduction in their bioavailability (see section 4.4).

Ketoconazole, itraconazole and erlotinib

The absorption of ketoconazole, itraconazole and erlotinib from the gastrointestinal tract is enhanced by the presence of gastric acid. Administration of DEXILANT may result in sub-therapeutic concentrations of ketoconazole, itraconazole and erlotinib, and the combination should be avoided.

Digoxin

Co-administration of DEXILANT and digoxin may lead to increased digoxin plasma levels. The plasma levels of digoxin should therefore be monitored, and the dose of digoxin adjusted if necessary when initiating and ending DEXILANT treatment.

Medicinal products metabolised by P450 enzymes

In vitro studies have shown that DEXILANT is not likely to inhibit CYP isoforms 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1 or 3A4. As such, no clinically relevant interactions with medicinal products metabolised by these CYP enzymes would be expected. Furthermore, in vivo studies showed that DEXILANT did not have an impact on the pharmacokinetics of co-administered phenytoin (CYP2C9 substrate) or theophylline (CYP1A2 substrate). The subjectsu2019 CYP1A2 genotypes in the drug-drug interaction study with theophylline were not determined. Although in vitro studies demonstrated that DEXILANT has the potential to inhibit CYP2C19, an in vivo drug-drug interaction study in mainly CYP2C19 extensive and intermediate metabolisers has shown that DEXILANT does not affect the pharmacokinetics of diazepam (CYP2C19 substrate).

Tacrolimus

Co-administration of DEXILANT may increase the plasma concentrations of tacrolimus (a CYP3A and P-glycoprotein [P-g p] substrate), especially in transplant patients who are intermediate or poor metabolisers of CYP2C19. Monitoring of tacrolimus plasma concentrations is advised when concomitant treatment with DEXILANT is initiated or ended.

Warfarin

Co-administration of DEXILANT and warfarin did not result in any significant differences in the pharmacokinetics of warfarin or International Normalised Ratio (INR) compared to administration of warfarin with placebo. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time, especially when initiating or ending concomitant treatment.

Clopidogrel

Concomitant administration of DEXILANT (60 mg once daily) and clopidogrel 75 mg to healthy volunteers resulted in a reduction in the exposure to the active metabolite of clopidogrel (approximately 9 % decrease in AUC and 27 % decrease in C max). Co-administration of DEXILANT had no clinically meaningful effect on pharmacodynamics of clopidogrel. No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT.

Methotrexate

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate possibly leading to methotrexate toxicities. Therefore, in settings where high-dose methotrexate is used a temporary withdrawal of DEXILANT may need to be considered. However, no formal drug interaction studies of high-dose methotrexate with PPIs have been conducted.

PPIu2019s including DEXILANT are contra-indicated with rilpirivine-containing products.

Medicinal products transported by P-glycoprotein

DEXILANT may inhibit the transport protein, P-g p

Others

No clinically significant interactions of DEXILANT with nonsteroidal anti-inflammatory drugs have been demonstrated, although no formal interactions studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is limited amount of data from the use of DEXILANT in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of DEXILANT during pregnancy.

Breastfeeding

It is not known whether DEXILANT is excreted in human breast milk. Animal studies have shown excretion of lansoprazole in milk. A risk to the newborns/infants cannot be excluded. DEXILANT should not be used during breastfeeding

Fertility

There was no evidence of impaired fertility following the administration of lansoprazole in animal studies (see section 5.3). Similar results could be expected with DEXILANT

4.7 Effects on ability to drive and use machines

Instances of dizziness, vertigo, visual disturbances and somnolence have been reported with DEXILANT. Patients who are experiencing these adverse events should not drive or use machines. Under these conditions the ability to react may be decreased.

4.8 Undesirable effects

Summary of the safety profile

Adults

DEXILANT at doses of 30, 60, or 90 mg has been evaluated for safety in clinical studies in patients treated for up to 1 year. In these clinical studies, adverse reactions associated with treatment with DEXILANT were mostly mild or moderate, with an overall incidence similar to placebo and lansoprazole. The most commonly reported adverse reactions were diarrhoea, abdominal pain, headache, nausea, abdominal discomfort, flatulence and constipation. The incidence of these adverse reactions was not affected by gender, age, or race.

Tabulated list of adverse reactions

Adverse reactions reported for DEXILANT (30 mg, 60 mg or 90 mg) in clinical studies and post-marketing experience are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class

Common

Uncommon

Rare

Not known

Blood and lymphatic system disorders

Autoimmune haemolytic anaemia 1,2

Idiopathic thrombocytopenic purpura 2

Immune system disorders

Anaphylactic reaction 2

Hypersensitivity 1,2

Anaphylactic shock 2

Metabolism and connective tissue disorders

Hypomagnesaemia 2 (see section 4.4)

Hyponatraemia 2

Hypocalcaemia 2,3

Hypokalaemia 2,3

Musculoskeletal and connective tissue disorders

Fracture of the hip, wrist or spine (see section 4.4)

Psychiatric disorders

Insomnia

Depression

Auditory hallucinations

Visual hallucinations

Nervous system disorders

Headache

Dizziness

Altered taste

Convulsion

Paraesthesia

Eye disorders

Visual disturbance

Blurred vision 2

Ear and labyrinth disorders

Vertigo

Deafness 2

Vascular disorders

Hypertension

Hot flushes

Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Diarrhoea 1

Abdominal pain 1

Nausea

Abdominal discomfort

Flatulence

Constipation

Vomiting

Dry mouth

Candidiasis

Fundic gland polyps (benign)

Hepatobiliary disorders

Liver function test abnormal

Hepatitis drug-induced 2

Skin and subcutaneous tissue disorders

Urticaria

Pruritus

Rash

Subacute cutaneous lupus erythematosus (see section 4.4)

Stevens-Johnson syndrome 2

Toxic epidermal necrolysis 2

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 2

Erythema multiforme

Renal and urinary disorders

Tubulointerstitial nephritis 2 (with possible progression that may lead to chronic renal failure)

General disorders and administration site conditions

Asthenia

Appetite changes

1 see section u2018Description of selected adverse reactionsu2019

2 adverse reactions that have been observed during post approval of dexlansoprazole (as these reactions are reported voluntarily from a population of uncertain size, frequency cannot be estimated from the available data)

3 Hypocalcaemia and/or hypokalaemia may be related to the occurrence of hypomagnesaemia (see section 4.4)

Description of selected adverse reactions

Diarrhoea and abdominal pain

In the Phase 3 clinical studies, the most commonly reported adverse reaction was diarrhoea (excluding infective diarrhoea), the majority of which were non serious. Overall, few subjects (2,4 %) prematurely discontinued due to an adverse reaction while receiving DEXILANT therapy. The most common (u2265 0 ,5 %) adverse reactions leading to premature discontinuation were diarrhoea, gastrointestinal and abdominal pains. Initial onset of diarrhoea and abdominal pain was independent of the duration of exposure, and the majority of these events were mild to moderate in severity. There were no apparent dose-related trends observed across DEXILANT doses for the incidence of these events.

Hypersensitivity

There have been post-marketing cases reporting serious hypersensitivity reactions. Hypersensitivity reactions were more frequently reported in females (74 %). The majority of the serious cases were managed with steroids and/or antihistamines and withdrawal of the medicinal product. Severe reactions of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Drug reaction with eosinophilia and systemic symptoms (DRESS) and erythema multiforme were reported in few patients.

Haemolytic anaemia

There have been few serious post-marketing reports of haemolytic anaemia after approximately four to seven months on DEXILANT 60 mg therapy.

Paediatric population

The safety profile for adolescents aged 12 to 17 years is similar to adults. In clinical studies of 166 adolescent patients, the only adverse reaction that occurred in more than one patient was abdominal pain. Additional adverse reactions, which occurred in one patient each, included diarrhoea, urticaria, dry mouth and headache.

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 Adverse Drug Event Monitoring Centre or Pharmacovigilance unit at SAHPRA. using the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8. Additionally, suspected adverse reactions can be reported to [email protected]

4.9 Overdose

In the case of suspected overdose, the patient should be monitored. DEXILANT is not significantly eliminated by haemodialysis. If necessary, charcoal and symptomatic therapy is recommended.