Dilazol

Effects of omeprazole on the pharmacokinetic of other active substances

Active substances with pH dependent absorption

The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.

Nelfinavir, atazanavir
The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole.
Concomitant administration of omeprazole with nelfinavir is contraindicated. Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75-90%. The interaction may also involve CYP2C19 inhibition.

Concomitant administration of omeprazole with atazanavir is not recommended. Concomitant administration or omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure 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 to atazanavir 300 mg/ritonavir 100 mg once dally.

Digoxin
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced.

Clopidogrel
In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite or clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together.

In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the Inhibitory effect of omeprazole on CYP2C19.
Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.

Other active substances
The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided.

Active substances metabolised by CYP2C19
Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.

Cilostazol
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.

Phenytoin

Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment.
Unknown mechanism

Saquinavir
Concomitant administration of omeprazole with Saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for Saquinavir associated with good tolerability in HIV-infected patients.

Tacrolimus
Concomitant administration of omeprazole 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.

Effect of other active substances on the pharmacokinetics of omeprazole
Inhibitors CYP2C19 and for CYP3A4

Since omeprazole is metabolised by CYP2C19 and CYP3A4 active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole’s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubting or the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Inducers of CYP2C19 and/or CYP3A4
Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John’s wort ) may lead lo decreased omeprazole serum levels by Increasing omeprazole’s rate of metabolism.

Blood and lymphalic system disorders Rare: Leucopenia, thrombocytopenia, agranulocytosis, pancytopenia

Endocrine disorders Rare: Gynaecomastia

Metabolic and nutritional disorders Rare: Hyponatraemia

Psychiatric disorders Rare: Reversible mental confusion, agitation, aggression, depression and hallucinations (predominantly in severely ill patients)

Nervous system disorders
Common: Headache (severe enough to cause discontinuation in some patients)
Uncommon: Dizziness. somnolence, insomnia, parasthaesias

Eye disorders Rare: Blurred vision.

Vascular disorders Rare: Peripheral oedema

Respiratory, thoracic and mediastinal disorders Rare: Bronchospasm

Gastrointestinal disorders
Common: Diarrhoea (severe enough to require discontinuation of therapy in some patients), constipation, abdominal pain or colic, nausea, vomiting, flatulence
Rare: Dry mouth, stomatitis, oesophageal candidiasis, taste disturbances

Hepato-biliary disorders
Uncommon: Raised liver enzymes Rare: Hepatitis with or without jaundice, hepatic encephalopathy

Skin and subcutaneous tissue disorders
Uncommon: Skin rash, urticaria, pruritus
Rare: Photosensitivity, bullous eruption, toxic epidermal necrolysis, Stevens-Johnson syndrome, alopecia, erythema multiforme

Musculoskeletal, connective tissue and bone disorders Rare: Asthenia, arthralgia, myalgia

Renal and urinary disorders Rare: Interstitial nephritis

Other
Uncommon: Malaise Rare: Hypersensitivity reactions (e.g. fever, angioedema, bronchospasm, interstitial nephritis) and anaphylactic shock

OVERDOSE/TOXICITY:
There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose).

Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases.

The symptoms described have been transient and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic.

Paediatric use.
Children over 1 year of age and ≥10 kg
• Treatment of reflux esophagitis
• Symptomatic treatment of heart burn and acid regurgitation in gastro-oesophageal reflux disease.

Children and adolescents over 4 years of age
In combination with antibiotics in treatment of duodenal ulcer caused by H. pylori.

ADMINISTRATION ANO DOSAGE:
DlLAZOL is recommended to be given in the morning and swallowed whole with a half glass of liquid. The capsules should not be chewed or crushed.

RECOMMENDED DOSAGES FOR ADULTS
Duodenal ulcer
20 mg once daily for two to four weeks.

In some duodenal ulcer patients refractory to other treatment regimens, 40 mg once daily may be effective.
Prevention of relapse in patients with duodenal ulcer
10 mg once daily.

If necessary the dose can be increased to 20-40 mg once daily.
The above recommended dosage regimens are inclusive of Helicobacter pylori-positive duodenal ulcers as part of the eradication programme with appropriate antibiotics. Gastric ulcer and reflux oesophagitis

20 mg once daily for four to eight weeks.
In some gastric ulcer and reflux oesophagitis patients refractory to other treatment regimens, 40 mg once daily may be effective.

For the long-term management of patients with reflux oesophagitis the recommended dose is 20 mg once daily. If necessary the dose can be increased to 20 -40 mg once daily. In patients with severe or symptomatic recurrent reflux oesophagitis treatment can be continued with DILAZOL at a dosage of 20 mg once daily.

NSAID-associated gastro-duodenal lesions with or without continued NSAID treatment.
20 mg once daily.
In most patients healing occurs within 4 weeks. For patients who may not be fully healed after the Initial course healing usually occurs during a further 4 weeks of treatment.

Prevention of NSAID-associated gastro-duodenal lesions and dyspeptic symptoms 20 mg once daily
Symptomatic gastro-esophageal reflux disease 20 mg daily.

Patients may respond adequately to 10 mg daily, therefore individual dose adjustments should be considered.
If symptom control has not been achieved after 2 weeks of treatment with 20 mg daily further investigation is recommended.
Zollinger-Ellison Syndrome
60 mg once daily.

The dosage should be adjusted individually and treatment continued as long as it is clinically indicated with doses above 80 mg daily the dose should be divided and given twice daily.
There is very limited experience with the use of DILAZOL in children.
Severe ulcerative reflux oesophagitis in children from one year and older

Recommended dosages:

Elderly

Dose reductions are not necessary in elderly patients.
The long-term safety of DILAZOL in patients with renal and hepatic impairment has not been established (see WARNINGS).

Impaired renal function
Dose reductions are not necessary in renal impairment.

Impaired hepatic function
Bioavailability and plasma half-life of DILAZOL are increased in patients with impaired hepatic function, therefore a daily dose of 10 -20 mg is generally sufficient.