Zosa DSR Capsules

Esomeprazole (GR) & Domperidone (PR) Capsules

Each hard gelatin capsule contains:

Esomeprazole Magnesium (Trihydrate) IP

equivalent to Esomeprazole …………………. 40 mg

(as gastro-resistant pellets)

Domperidone IP …………………………………… 30 mg

(as prolonged release pellets)

Capsules, Esomeprazole (GR) & Domperidone (PR) [40 mg + 30 mg]

4.1 Therapeutic indication

For the treatment of adult patients with GERD (gastro esophageal reflux disease) not responding to esomeprazole alone.

4.2 Posology and method of administration

One capsule once daily.

Use in Special Populations

• Pediatric

Zosa DSR Capsules is not recommended in children below 12 years of age.

• Hepatic impairment

For patients with severe liver impairment, a maximum dose of 20 mg of esomeprazole should not be exceeded.

Domperidone is contraindicated in moderate or severe hepatic impairment.

Hence, Zosa DSR Capsules is contraindicated in patients with moderate or severe hepatic impairment.

• Renal impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, Zosa DSR Capsules should be used with caution in patients with severe renal insufficiency. Patients on prolonged therapy should be reviewed regularly.

4.3 Contraindications

Zosa DSR Capsules is contraindicated in the following situations

• Known hypersensitivity to the active substance esomeprazole and domperidone, to substituted benzimidazoles or to any of the excipients listed in formulation.
• Prolactin-releasing pituitary tumour (prolactinoma)
• In patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

This formulation should not be used when stimulation of gastric motility could be harmful: gastro-intestinal haemorrhage, mechanical obstruction or perforation.

4.4 Special warnings and precautions for use

• Symptomatic response to therapy with esomeprazole does not preclude the presence of gastric malignancy.
• Therapy with esomeprazole may be associated with Clostridium difficile associated diarrhea. Patients should use the lowest dose and shortest duration of PPI therapy appropriate.
• Atrophic Gastritis has been noted occasionally in gastric corpus biopsies from patients on long-term treatment with esomeprazole.
• For patients expected to be on prolonged esomeprazole treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically thereafter.
• PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
• Serum chromogranin A (CgA) levels increase secondary to esomeprazole-induced decrease in gastric acidity. This may cause false-positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high.
• Domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. Caution is exercised in patients who have existing prolongation of cardiac conduction intervals, electrolyte disturbances or underlying cardiac diseases.
• The risk of neurological side effects with domperidone is higher in young children. Overdosing may cause extra-pyramidal symptoms.

4.5 Drugs interactions

Esomeprazole

Effects of esomeprazole on the pharmacokinetics of other medicinal products

Protease inhibitors

Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP 2C19.

For atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, C_max and C_min). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg once daily. Co-administration of omeprazole (40 mg once daily) reduced mean nelfinavir AUC, C_max, and C_min by 36–39 % and mean AUC, C_max and C_min for the pharmacologically active metabolite M8 was reduced by 75-92%. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated.

For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg once daily). Treatment with omeprazole 20 mg once daily had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg once daily had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg once daily had no effect on the exposure of lopinavir (with concomitant ritonavir).

Methotrexate

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

Tacrolimus

Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.

Medicinal products with pH dependent absorption

Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as ketoconazole, atazanavir, iron salts, mycophenolate mofetil (MMF), itraconazole, and erlotinib can decrease and the absorption of digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic medicinal product monitoring of digoxin should then be reinforced.

Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole and MMF. Use esomeprazole with caution in transplant patients receiving MMF.

Medicinal products metabolised by CYP2C19

Esomeprazole inhibits CYP2C19, the major esomeprazole-metabolising enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these medicinal products may be increased, and a dose reduction could be needed.

This should be considered especially when prescribing esomeprazole for on-demand therapy.

Diazepam

Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.

Phenytoin

Concomitant oral administration of 40 mg esomeprazole and phenytoin resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

Voriconazole

Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUCτ by 15% and 41%, respectively.

Cilostazol

Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.

Cisapride

In healthy volunteers, concomitant oral administration of 40 mg esomeprazole and cisapride resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t1/2) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole.

Warfarin

Concomitant oral administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing of oral esomeprazole, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.

Clopidogrel

Results from studies in healthy subjects have shown a pharmacokinetic (PK)/ pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40% and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%.

When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups.

Inconsistent data on the clinical implications of a PK/PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution concomitant use of clopidogrel should be discouraged.

Investigated medicinal products with no clinically relevant interaction

Amoxicillin or quinidine

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.

Naproxen or rofecoxib

Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Effects of other medicinal products on the pharmacokinetics of esomeprazole

Medicinal products which inhibit CYP2C19 and/or CYP3A4

Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubling of the exposure (AUC) to esomeprazole.

Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP 3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUCτ by 280%. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Medicinal products which induce CYP2C19 and/or CYP3A4

Medicinal products known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism. Avoid concomitant use of St. John’s Wort or rifampin with esomeprazole.

Pediatric population

Interaction studies have only been performed in adults.

Domperidone

The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.

Concomitant use of the following substances is contraindicated

QTc prolonging medicinal products

• anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)
• anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
• certain anti-psychotics (e.g., haloperidol, pimozide, sertindole)
• certain anti-depressants (e.g., citalopram, escitalopram)
• certain antibiotics (e.g. erythromycin, levofloxacin, moxifloxacin, spiramycin)
• certain antifungal agents (e.g., pentamidine)
• certain antimalarial agents (in particular halofantrine, lumefantrine)
• certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)
• certain antihistaminics (e.g., mequitazine, mizolastine)
• certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)
• certain other medicines (e.g., bepridil, diphemanil, methadone)

(see section Contraindications).

• apomorphine, unless the benefit of the co-administration outweighs the risks, and only if the recommended precautions for co-administration are strictly fulfilled.

Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e.:

• protease inhibitors
• systemic azole antifungals
• some macrolides (erythromycin, clarithromycin, telithromycin)

Concomitant use of the following substances is not recommended

Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides.

Concomitant use of the following substances requires caution in use

Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation: azithromycin and roxithromycin (clarithromycin is contra-indicated as it is a potent CYP3A4 inhibitor).

The above list of substances is representative and not exhaustive.

Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs.

With the combination of oral domperidone 10 mg four times daily and ketoconazole 200 mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10 mg four times daily and oral erythromycin 500 mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10 mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200 mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

4.6 Use in special populations

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Zosa DSR capsules should be used during pregnancy only if clearly needed.

Lactation

Domperidone is excreted in human milk and breast-fed infants receive less than 0.1% of the maternal weight-adjusted dose. Caution should be exercised when Zosa DSR Capsules is administered to a nursing mother.

4.7 Effects on ability to drive and use machines

Zosa DSR has minor influence on the ability to drive and use machines. Adverse reactions such as dizziness (uncommon) and blurred vision (rare) have been reported. If affected patients should not drive or use machines.

4.8 Undesirable effects

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 email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Overdose with 280 mg of esomeprazole were associated with gastrointestinal symptoms and weakness. Symptoms with domperidone over dosage may include agitation, altered consciousness, convulsions, disorientation, somnolence and extra pyramidal reactions. There is no specific antidote to esomprazole and domperidone.

In case of overdose, standard symptomatic treatment should be given immediately. Gastric lavage as well as the administration of activated charcoal may be useful. ECG monitoring should be undertaken. Close medical supervision and supportive therapy is recommended. Anticholinergic, anti-parkinson drugs may be helpful in controlling the extra pyramidal reactions seen with domperidone.

5.1 Mechanism of action

Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K + -ATPase – the acid pump and inhibits both basal and stimulated acid secretion.

Domperidone binds to dopamine receptor D2 (D2R) expressed by peripheral neurons; this inhibits dopamine binding and D2R-mediated signaling. Inhibition of peripheral D2R signaling prevents or relieves various gastrointestinal (GI) symptoms, such as nausea and vomiting, and may help relief reflux and symptoms of a variety of other upper GI disorders.

5.2 Pharmacodynamic properties

Esomeprazole

After 5 days of oral dosing with esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively was 97%, 92% and 56%. Healing of reflux oesophagitis with esomeprazole occurs in approximately 78% of patients after 4 weeks, and in 93% after 8 weeks. During treatment with antisecretory medicinal products, serum gastrin and Chromogranin A (CgA) increases in response to the decreased acid secretion. Gastric glandular cysts have been reported to occur at a some what increased frequency on long-term treatment. These changes are benign and appear to be reversible.

Domperidone

Domperidone does not readily cross the blood brain barrier. In domperidone users, especially in adults, extra pyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Studies have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

When domperidone was administered in healthy subjects at up to 80 mg/day (i.e., more than twice the maximum recommended dosing) in QT study performed in accordance with ICH-E14 guidelines, no clinically relevant QTc effects were observed.

5.3 Pharmacokinetic properties

6.1 Animal Toxicology or Pharmacology

Esomeprazole

Carcinogenicity: The carcinogenic potential of esomeprazole magnesium was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7 mg/kg/day, 3.4 mg/kg/day, 13.8 mg/kg/day, 44 mg/kg/day, and 140.8 mg/kg/day (about 0.4 to 34 times the human dose of 40 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole.

In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human dose of 40 mg/day on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group.

Mutagenesis: Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test.

Impairment of Fertility: The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

Reproduction Studies: Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole.

Domperidone

Safety margins in in vitro proarrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 9- up to 45-fold. In in vivo models the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitized for torsade de pointes exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more than 22-fold and 435-fold, respectively. In the anesthetized guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4ng/ml, which are 3-fold higher than the total plasma levels in humans at maximum daily dose (10 mg administered 3 times a day).

At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits. Development abnormalities observed in rats at a high exposure. Risk of carcinogenicity, mutagenicity or sensitization cannot be excluded.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

8.4 Storage and handing instructions

Store protected from light & moisture at a temperature not exceeding 30°C.

Keep out of reach of children.

• Instruct patients to take ZOSA DSR Capsules exactly as prescribed by doctor. Do not change the dose or stop therapy without consulting to your doctor.
• Instruct patients to swallow ZOSA DSR Capsules whole with water on empty stomach, preferably in the morning or at least 1 hour before meal. The capsules should not be opened, chewed or crushed. 
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take 2 capsules/doses at the same time to make up for the missed dose.
• Pregnant women can use this medicine only if essential and in consultation with their doctor.
• Advise nursing mothers to avoid use of this medicine during lactation or not to breastfeed their infants while on drug therapy.
• This medicine is not recommended for use in children.
• Instruct patients not to share this medication with other people even though symptoms are similar. It may harm them.
• Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. ZOSA DSR Capsules and certain other medicines can interact with each other causing serious side effects.

17.09.2022