DicloDuo Combi: composition and form
DicloDuo Combi is a hard modified-release capsule holding two medicines at once. It contains 75 mg of diclofenac sodium, split into two portions: 25 mg in gastro-resistant pellets and 50 mg in prolonged-release pellets. Of omeprazole it holds 20 mg, also in gastro-resistant pellets. That construction means the substances do not come out at the same time, and not in the stomach.
Hence the handling rule: the capsule is swallowed whole with liquid, preferably with a meal. Neither splitting it nor tipping out the contents is envisaged by the product information — the pellet coating is precisely the mechanism that spreads release over time.
How DicloDuo Combi works
The point of the combination is that one substance treats while the other covers the consequences of the first. Diclofenac is a non-steroidal compound with marked analgesic and anti-inflammatory action, an inhibitor of prostaglandin synthetase, that is, of cyclo-oxygenase. Suppressing prostaglandin synthesis takes away joint pain and inflammation, but those same prostaglandins protect the gastric mucosa — and there lies the source of the main risk of the whole NSAID class.
Omeprazole solves the second task. It is a racemic mixture of two enantiomers and a proton pump inhibitor: a weak base that accumulates in the sharply acidic environment of the secretory canaliculi of the parietal cells and there inhibits the activity of H+/K+-ATPase. Its effect on the final stage of hydrochloric acid formation is dose-dependent and quenches both basal and stimulated secretion; the action comes on quickly and, taken once a day, keeps symptoms under control.
Indications
The indication is framed not only by diagnosis but also by patient profile. The medicine is used for the symptomatic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis — and specifically in those patients whose risk of gastric and duodenal ulcers after NSAIDs is raised. This capsule is chosen not because the diclofenac in it is stronger, but because the person to be treated has a vulnerable stomach.
Hence, too, what the medicine is not. It is not a remedy for one-off pain: behind the word "symptomatic" stands long treatment of a chronic joint disease. Nor is it a stomach medicine: omeprazole sits here at a fixed dose of 20 mg for a single task — to reduce the risk created by the other half of the capsule.
Administration and dosage
Adults are given 1 capsule a day, which corresponds to 75 mg of diclofenac and 20 mg of omeprazole. The upper limit is set not by diclofenac but by its partner: more than one capsule a day must not be taken, because it would lead to excessive exposure to omeprazole. If once-daily dosing does not settle the symptoms, the regimen is not reinforced but changed — to one or more alternative products. The course is kept as short as symptom control allows and is stopped if there is no benefit.
Special groups are described by the degree of organ damage. Diclofenac is largely excreted by the kidneys, so with impaired renal function the risk of toxic reactions is higher: mild and moderate impairment call for caution and monitoring, severe impairment is a contraindication. With the liver the logic is the same. Over the age of 65 the risk of serious consequences of adverse reactions is higher, so the smallest effective dose is used for the shortest possible time and patients are checked regularly for gastrointestinal bleeding. It is not recommended under 18: safety data are lacking.
Contraindications
Part of the prohibitions follows from the damage NSAIDs do to the digestive tract. The medicine is not given in active peptic ulcer disease, with two or more confirmed episodes of ulceration or bleeding in the past, or where bleeding or perforation has already occurred on NSAIDs. The second group is cardiovascular: congestive heart failure of NYHA class II-IV, ischaemic heart disease, peripheral vascular disease and cerebrovascular disorders.
The third group is set by the organs the medicine passes through and is cleared by: severe hepatic, renal and cardiac failure. The fourth is allergic: hypersensitivity to the active substances, to substituted benzimidazoles or to any excipient, and previous reactions — asthma, urticaria, angioedema, rhinitis — after ibuprofen, acetylsalicylic acid or other NSAIDs. Two points stand apart: the third trimester of pregnancy, and nelfinavir, with which omeprazole must not be given.
Special warnings and precautions
A large share of the warnings belongs to diclofenac. Allergic reactions are possible even without previous exposure to the medicine, and the medicine itself can mask the signs of an infection. It should not be combined with other NSAIDs: there is no evidence that the benefits add up, whereas the adverse effects do. In people with asthma, allergic rhinitis or COPD, reactions to NSAIDs — worsening asthma, Quincke's oedema, urticaria — occur more often. Bleeding, ulceration and perforation of the digestive tract can arise at any point in treatment and are not necessarily preceded by warning symptoms. The risk of heart attack and stroke rises slightly with high doses and long use, and on long treatment liver function is monitored: hepatitis begins without any herald.
The second half of the warnings is about omeprazole and about what it is able to conceal. Unintended weight loss, repeated vomiting, difficulty swallowing, vomiting of blood or tarry stools call for a tumour to be excluded: treatment softens the picture and can delay the diagnosis. Suppressing acidity reduces the absorption of vitamin B12. In people given proton pump inhibitors for at least three months, severe hypomagnesaemia has been described — fatigue, tetany, seizures, arrhythmias — which builds up unnoticed, so on long treatment magnesium is measured before the start and periodically afterwards. Taking high doses for more than a year raises the risk of hip, wrist and spine fractures by 10-40%. Subacute cutaneous lupus erythematosus has also been described. A rise in chromogranin A distorts testing for neuroendocrine tumours, so omeprazole is withdrawn five days before the assay. Dizziness and visual disturbance are possible from both components — with them one does not drive.
Interactions with other medicines
On the diclofenac side the interactions group around the kidneys, the blood and hepatic metabolism. Diuretics and ACE inhibitors raise the risk of nephrotoxicity: the patient must be adequately hydrated and renal function monitored; the diuretics and antihypertensives themselves grow weaker, while potassium-sparing diuretics push up serum potassium. Digoxin and lithium concentrations rise and both are monitored. NSAIDs within 24 hours before or after methotrexate require caution: diclofenac slows its excretion by the renal tubules. Oral corticosteroids, anticoagulants, antiplatelet agents and SSRIs increase the risk of bleeding; quinolones, the likelihood of seizures. Colestipol and cholestyramine slow absorption: the capsule is taken an hour before them or 4-6 hours after.
On the omeprazole side the reckoning runs in percentages, and the figures are large. Lowering acidity changes the absorption of pH-dependent substances: exposure to nelfinavir falls by about 40% and that of its active metabolite by 75-90%, so the combination is forbidden; atazanavir loses up to 75%, and raising its dose to 400 mg does not compensate; posaconazole, erlotinib, ketoconazole and itraconazole are absorbed worse. As a moderate CYP2C19 inhibitor, omeprazole strengthens the action of R-warfarin, cilostazol, diazepam and phenytoin. Clopidogrel is a story of its own: exposure to its active metabolite fell by 46% on day one and by 42% on day five, and inhibition of platelet aggregation by 47% and 30%, with separating the doses in time offering no rescue. Saquinavir, conversely, gains about 70%, and tacrolimus and methotrexate concentrations rise. Voriconazole more than doubles exposure to omeprazole, while rifampicin and St John's wort lower it.
Pregnancy and breastfeeding
The two components behave differently here, and the stricter one decides. Suppressing prostaglandin synthesis can adversely affect the course of pregnancy and the development of the fetus: epidemiological data point to a raised risk of miscarriage, cardiac malformations and gastroschisis with early use, the absolute risk of cardiovascular malformations rising from below 1% to about 1.5%. In the first and second trimesters diclofenac is not used unless absolutely necessary. In the third it is contraindicated: the fetus is threatened by premature closure of the ductus arteriosus with pulmonary hypertension and by renal impairment up to failure with oligohydramnios, and the mother and newborn by an antiplatelet effect even from small doses and by inhibition of uterine contractions.
More is known about omeprazole: three prospective studies covering over a thousand exposures showed no adverse effect on pregnancy or on the state of the fetus, and on its own it is permitted in pregnancy. It passes into milk, but at therapeutic doses poses no threat to the child. The restriction again comes from the NSAID: these pass into breast milk in very small amounts and are avoided during breastfeeding where possible. There is a third thread as well — fertility: the medicine may impair a woman's ability to conceive, so it is not recommended for those planning a pregnancy.
Adverse reactions
The adverse reactions of this capsule have to be read in two columns: the lists for diclofenac and omeprazole differ both in content and in frequency. They converge where blood, skin and liver are concerned.
| System | Diclofenac | Omeprazole |
| Blood | very rarely: leucopenia, neutropenia, haemolytic anaemia | rarely: leucopenia; very rarely: agranulocytosis, pancytopenia |
| Nervous system | commonly: headache; very rarely: aseptic meningitis, seizures | commonly: headache; uncommonly: paraesthesia, drowsiness |
| Digestive tract | commonly: nausea, diarrhoea, dyspepsia; rarely: ulcers and bleeding | commonly: abdominal pain, constipation, flatulence; rarely: dry mouth |
| Liver | commonly: rise in transaminases; rarely: jaundice, hepatitis; very rarely: necrosis | uncommonly: rise in enzymes; very rarely: hepatic failure |
| Skin | commonly: rash; very rarely: Stevens-Johnson syndrome, Lyell's syndrome | uncommonly: dermatitis, itching, urticaria; frequency unknown: cutaneous lupus |
| Kidneys and metabolism | very rarely: interstitial nephritis, acute failure | rarely: nephritis, hyponatraemia; frequency unknown: hypomagnesaemia |
| Heart and vessels | rarely: oedema; very rarely: hypertension, arterial thrombotic events | uncommonly: peripheral oedema; rarely: sweating |
The table had no room for the rare anaphylactoid reactions to diclofenac with a fall in blood pressure and shock, the airway reactions up to bronchospasm, and the very rare depression, insomnia and nightmares. For omeprazole, hip, wrist and spine fractures are uncommon, and aggression and hallucinations very rare.
Overdose
The main danger comes from diclofenac. Its excess shows itself as headache, nausea, vomiting, pain in the upper abdomen, gastrointestinal bleeding and, less often, disorientation, agitation, tinnitus, fainting and sometimes seizures; in severe poisoning acute renal failure and liver damage develop. Treatment is supportive and symptomatic: within an hour of taking a toxic amount activated charcoal is considered and, in adults with a life-threatening overdose, gastric lavage.
Thereafter diuresis and renal and hepatic function are watched and the patient is observed for at least four hours; for prolonged seizures diazepam is given intravenously. Forced diuresis, dialysis and haemoperfusion are most likely useless for clearing NSAIDs — these substances bind strongly to proteins. On omeprazole there is little data: doses up to 560 mg have been described, with isolated reports of a single oral intake of up to 2400 mg, 120 times the recommended dose. Nausea, vomiting, dizziness, abdominal pain and headache were recorded, and in isolated cases apathy and confusion; all of it was transient. Increasing the dose did not change the rate of elimination — the kinetics remain first-order — and treatment is purely symptomatic.
How to get a prescription for DicloDuo Combi online
This capsule has a narrow addressee: it is prescribed to those who need anti-inflammatory treatment but whose stomach tolerates that treatment badly, so the doctor needs two histories at once — the joint one and the gastric one. At e-zdrowie.com you fill in a medical questionnaire, the doctor examines the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and with it any Polish pharmacy will dispense the capsules.
In the questionnaire give the diagnosis for which the NSAID is needed and what you were treated with before. Be sure to list everything to do with the digestive tract: ulcers, bleeding, perforations, episodes that occurred on painkillers, ulcerative colitis and Crohn's disease. Report heart and vascular disease, hypertension, a past heart attack or stroke, liver and kidney disease, asthma and reactions to ibuprofen or acetylsalicylic acid, pregnancy and breastfeeding. List the medicines separately — anticoagulants and antiplatelet agents, clopidogrel, corticosteroids, SSRIs, diuretics, ACE inhibitors, methotrexate, digoxin, lithium and HIV drugs. It is exactly these points that decide whether the ready-made combination will do, or whether the doctor will prescribe the NSAID and the gastric protection separately.
