Summary of Product Characteristics (SmPC) - Elyxyb 120 mg oral solution in single-dose Container
1 NAME OF THE MEDICINAL PRODUCT
Elyxyb 120 mg oral solution in single-dose container
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 single-dose container (4.8 ml of oral solution) contains 120 mg of celecoxib.
Excipient(s) with known effect
1 single-dose container contains 960 mg of ethanol, 1200 mg of macrogolglycerol ricinoleate and 496 mg of macrogol hydroxystearate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Oral solution.
Clear, pale-yellow solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Elyxyb is indicated in adults for the acute treatment of migraine with or without aura.
4.2 Posology and method of administration
Posology
The recommended dose is 120 mg celecoxib.
The maximum dose in a 24-hour period is 120 mg. The safety and efficacy of a second dose in a 24-hour period have not been established.
The oral solution can be taken with or without food.
Special populations
Elderly Patients
In the elderly population (> 65 years old) with a body weight less than 50 kg, particular caution should be exercised (see sections 4.4 and 5.2). No dose recommendation can be provided.
Hepatic impairment
Use of Elyxyb in patients with severe hepatic impairment (Child-Pugh Class C) is contra-indicated.
Elyxyb has not been studied in patients with hepatic impairment and caution is advised when treating this patient population. No dose recommendation can be provided.
Renal impairment
Elyxyb is contra-indicated in patients with severe renal impairment.
Experience with celecoxib in patients with mild or moderate renal impairment is limited, therefore such patients should be treated with caution. No dose recommendation can be provided.
CYP2C9 poor metabolisers
In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3), based on genotyping or previous history/experience with other CYP2C9 substrates (e.g., warfarin, phenytoin), celecoxib should be administered with caution. No dose recommendation can be provided.
Paediatric population
Elyxyb is not indicated for use in children and adolescents.
Method of administration
Oral use.
Each single-dose container is intended for single use only.
After taking Elyxyb, a glass of water may be drunk.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Hypersensitivity to sulfonamides.
- Active peptic ulceration or gastrointestinal (GI) bleeding.
- Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors.
- In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6).
- Breast-feeding (see sections 4.6 and 5.3).
- Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10).
- Patients with estimated creatinine clearance <30 ml/min.
- Inflammatory bowel disease.
- Congestive heart failure (NYHA II-IV).
- Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
4.4 Special warnings and precautions for use
Elyxyb should only be used where there is a clear diagnosis of migraine. Elyxyb is not indicated for use in the management of hemiplegic, basilar or ophthalmoplegic migraine. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that migraineurs may be at risk of certain cerebrovascular events (e.g., CVA or TIA).
Elyxyb is not indicated for the preventive treatment of migraine.
Medication overuse headache (MOH)
Overuse of any type of medicinal products for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained, and treatment should be discontinued. The diagnosis of MOH should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.
Gastrointestinal (GI) effects
Upper and lower gastrointestinal complications (perforations, ulcers, or bleedings [PUBs]), some of them resulting in fatal outcome, have occurred in patients treated with celecoxib. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or antiplatelet medicinal products (such as acetylsalicylic acid) or glucocorticoids concomitantly, patients using alcohol, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.
There is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications) when celecoxib is taken concomitantly with acetylsalicylic acid (even at low doses).
A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.
Concomitant NSAID use
The concomitant use of celecoxib and a non-acetylsalicylic acid NSAID should be avoided.
Cardiovascular effects
NSAIDs, including COX-2 selective inhibitors, have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long-term.
The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk.
To minimize the potential risk for an adverse cardiovascular (CV) event in NSAID-treated patients, Elyxyb should be used for the fewest number of days per month as needed, based on individual treatment goals. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur (see sections 4.3, 4.8 and 5.1).
Patients with significant risk factors for cardiovascular events (e.g., hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration.
COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued (see section 5.1).
Fluid retention and oedema
Fluid retention and oedema have been observed in patients taking celecoxib. Therefore, celecoxib should be used with caution in patients with history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia.
Hypertension
Celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events.
Hepatic and renal effects
Compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically appropriate supervision should be maintained.
NSAIDs, including celecoxib, may cause renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, angiotensin converting enzyme (ACE)-inhibitors, angiotensin II receptor antagonists, and the elderly (see section 4.5).
Such patients should be carefully monitored while receiving treatment with celecoxib.
Some cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis and, hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib. Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib treatment (see section 4.8).
If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken, and discontinuation of celecoxib therapy should be considered.
CYP2D6 inhibition
Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for individually dose-titrated medicinal products that are metabolised by CYP2D6 (see section 4.5).
CYP2C9 poor metabolisers
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2).
Skin and systemic hypersensitivity reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of celecoxib (see section 4.8). Fixed drug eruption (FDE) which may present as a more severe variant known as generalised bullous fixed drug eruption (GBFDE) has also been reported in association with the use of celecoxib (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome), have been reported in patients receiving celecoxib (see section 4.8). Patients with a history of sulfonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see section 4.3). Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
General
Celecoxib may mask fever and other signs of inflammation.
Use with oral anticoagulants
In patients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Increased prothrombin time (INR) with concurrent therapy has been reported. Therefore, this should be closely monitored in patients receiving warfarin/coumarin-type oral anticoagulants, particularly when therapy with celecoxib is initiated (see section 4.5). Concomitant use of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should be exercised when combining celecoxib with warfarin or other oral anticoagulants, including novel anticoagulants (e.g., apixaban, dabigatran, and rivaroxaban).
Excipients
Elyxyb contains macrogolglycerol ricinoleate and macrogol hydroxystearate which may cause stomach upset and diarrhoea.
This medicine contains 960 mg of alcohol (ethanol) in each dose which is equivalent to 19.8% (w/v). The amount is equivalent to less than 24 ml beer or 10 ml wine.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Anticoagulants
Anticoagulant activity should be monitored particularly in the first few days after initiating or changing the dose of celecoxib in patients receiving warfarin or other anticoagulants since these patients have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, (see section 4.4). Bleeding events in association with increases in prothrombin time have been reported, predominantly in the elderly, in patients receiving celecoxib concurrently with warfarin, some of them fatal.
Anti-hypertensives
NSAIDs may reduce the effect of anti-hypertensive medicinal products including ACE-inhibitors, angiotensin II receptor antagonists, diuretics, and beta-blockers. As for NSAIDs, the risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g., dehydrated patients, patients on diuretics, or elderly patients) when ACE-inhibitors, angiotensin II receptor antagonists, and/or diuretics are combined with NSAIDs, including celecoxib (see section 4.4). Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated, and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
Ciclosporin and tacrolimus
Co-administration of NSAIDs and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be monitored when celecoxib and any of these medicinal products are combined.
Acetylsalicylic acid
Celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid for CV prophylaxis. In the submitted studies, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid (see section 5.1).
Pharmacokinetic interactions
Effects of celecoxib on other medicinal products
CYP2D6 inhibition
Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of medicinal products that are substrates of this enzyme may be increased when celecoxib is used concomitantly.
Examples of medicinal products which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmic medicinal products, anti-cough (Dextrometorphan) etc.
The dose of individually dose titrated CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or increased if treatment with celecoxib is terminated.
Methotrexate
In patients with rheumatoid arthritis celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic doses). However, adequate monitoring for methotrexate-related toxicity should be considered when combining these two medicinal products.
Lithium
NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dose while the combination is being taken and when the NSAID is withdrawn.
Oral contraceptives
In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg norethisterone/35 micrograms ethinylestradiol).
Glibenclamide/tolbutamide
Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant extent.
Effects of other medicinal products on celecoxib
CYP2C9 poor metabolisers
In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors such as fluconazole could result in further increases in celecoxib exposure. Such combinations should be avoided in known CYP2C9 poor metabolisers (see sections 4.2 and 5.2).
CYP2C9 inhibitors and inducers
Since celecoxib is predominantly metabolised by CYP2C9 it should be used at half the recommended dose in patients receiving fluconazole.
Co-administration of celecoxib with medicinal products that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g., rifampicin, carbamazepine, and barbiturates) may lead to compromised efficacy of Elyxyb.
Ketoconazole and antacids
Ketoconazole or antacids have not been observed to affect the pharmacokinetics of celecoxib.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
Studies in animals (rats and rabbits) have shown reproductive toxicity, including malformations (see sections 4.3 and 5.3). Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. The potential for human risk in pregnancy is unknown but cannot be excluded. Celecoxib may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester.
During the second or third trimester of pregnancy, NSAIDs including celecoxib may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible upon discontinuation.
Celecoxib is contraindicated in pregnancy and in women who can become pregnant (see section 4.3 ). If a woman becomes pregnant during treatment, celecoxib should be discontinued.
Breast-feeding
Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Administration of celecoxib to a limited number of breast-feeding women has shown a very low transfer of celecoxib into breast milk. Women who take celecoxib should not breastfeed.
Fertility
Based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.
4.7 Effects on ability to drive and use machines
Celecoxib may have minor influence on the ability to drive and use machines.
Dizziness, vertigo, somnolence, or weakness may occur as a result of migraine. This may influence the ability to drive and to operate machinery.
4.8 Undesirable effects
The safety of Elyxyb is based on data from two randomized, double-blind, placebo-controlled phase 3 clinical studies (Study 1 and Study 2) in adult patients with migraine with or without aura. A total of 815 subjects in the Any Active group were exposed to at least one dose of Elyxyb at any time during the studies. The most common treatment-emergent adverse events (TEAEs) in the Any Active group were less than 3% and presented in Table 1:
Table 1: Adverse drug reactions in celecoxib oral solution clinical trials (patients with migraine with or without aura)
| Adverse Drug Reaction Frequency | ||||||
| Systems organ class | Very common (≥ 1/10) | Common (≥ 1/100 to < 1/10) | Uncommo n (≥ 1/1,000 to < 1/100) | Rare (≥ 1/10,000 to < 1/1,000) | Very rare (< 1/10,000) | Not known (cannot be estimated from |
| available data) | ||||||
| Nervous system disorders | Dysgeusia Psychiatric disorders Insomnia | |||||
| Gastroint estinal disorders | Nausea Vomiting Diarrhoea |
The safety of celecoxib oral solution is also based on the known adverse reactions (Table 2) of celecoxib capsules in osteoarthritis patients and rheumatoid arthritis patients, in long-term polyp prevention trials and from post-marketing surveillance:
- Adverse reactions reported in osteoarthritis patients and rheumatoid arthritis patients at incidence rates greater than 0.01 % and greater than those reported for placebo during 12 placebo- and/or active-controlled clinical trials of duration up to 12 weeks at celecoxib daily doses from 100 mg up to 800 mg. In additional studies using non-selective NSAID comparators, approximately 7400 arthritis patients have been treated with celecoxib at daily doses up to 800 mg, including approximately 2300 patients treated for 1 year or longer. The adverse reactions observed with celecoxib in these additional studies were consistent with those for osteoarthritis and rheumatoid arthritis patients listed in Table 2.
- Adverse reactions reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg daily in long-term polyp prevention trials of duration up to 3 years (the Adenoma Prevention with Celecoxib (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials.
- Adverse drug reactions from post-marketing surveillance as spontaneously reported during a period in which an estimated >70 million patients were treated with celecoxib (various doses, durations, and indications). Even though these were identified as reactions from post-marketing reports, trial data was consulted to estimate frequency. Frequencies are based on a cumulative meta-analysis with pooling of trials representing exposure in 38102 patients.
Table 2: Adverse drug reactions in celecoxib capsules clinical trials and surveillance experience (MedDRA preferred terms)1,2
| Adverse Drug Reaction Frequency | ||||||
| System organ class | 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) | Very rare (< 1/10,000) | Not known (cannot be estimated from available data) |
Infections and infestations | Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection | |||||
| Blood and | Anaemia | Leukopenia, | Pancytopeni | |||
| Adverse Drug Reaction Frequency | ||||||
| System organ class | 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) | Very rare (< 1/10,000) | Not known (cannot be estimated from available data) |
| lymphatic system disorders | thrombo- cytopenia | a4 | ||||
| Immune system disorders | Hyper- sensitivity | Anaphylactic shock4, anaphylactic reaction4 | ||||
Metabolism and nutrition disorders | Hyperkalae mia | |||||
| Psychiatric disorders | Insomnia | Anxiety, depression, fatigue | Confusional state, hallucination s4 | |||
| Nervous system disorders | Dizziness, hypertonia, headache4 | Cerebral infarction1, paraesthesia, somnolence | Ataxia, dysgeusia | Haemorrhag e intracranial (including fatal intracranial haemorrhage )4, meningitis aseptic4, epilepsy (including aggravated epilepsy)4, ageusia4, anosmia4 | ||
Eye disorders | Vision blurred, conjunctiviti s4 | Eye haemorrhage 4 | Retinal artery occlusion4, retinal vein occlusion4 | |||
| Ear and labyrinth disorders | Tinnitus, hypoacusis1 | |||||
| Cardiac disorders | Myocardial infarction1 | Cardiac failure, palpitations, tachycardia | Arrhythmia4 | |||
| Vascular disorders | Hyper- tension1 (including aggravated hyper- | Pulmonary embolism4, flushing4 | Vasculitis4 | |||
| Adverse Drug Reaction Frequency | ||||||
| System organ class | 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) | Very rare (< 1/10,000) | Not known (cannot be estimated from available data) |
| tension) | ||||||
Respiratory, thoracic, and mediastinal disorders | Rhinitis, cough, dyspnoea1 | Bronchospas m4 | Pneumonitis4 | |||
Gastrointest inal disorders | Nausea4, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting1, dysphagia1 | Constipation , gastritis, stomatitis, gastrointesti nal inflammatio n (including aggravation of gastrointesti nal inflammatio n), eructation | Gastrointesti nal haemorrhage 4, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation, oesophagitis, melaena, pancreatitis, colitis4 | |||
| Hepatobilia ry disorders | Hepatic function abnormal, hepatic enzyme increased (including increased SGOT and SGPT) | Hepatitis4 | Hepatic failure4 (sometimes fatal or requiring liver transplant), hepatitis fulminant4 (some with fatal outcome), hepatic necrosis4, cholestasis4, hepatitis cholestatic4, jaundice4 | |||
| Adverse Drug Reaction Frequency | ||||||
| System organ class | 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) | Very rare (< 1/10,000) | Not known (cannot be estimated from available data) |
| Skin and subcutaneo us tissue disorders | Rash, pruritus (includes pruritus generalised) | Urticaria, ecchymosis4 | Angioedema 4, alopecia, photo- sensitivity | Dermatitis exfoliative4, erythema multiforme4, Stevens-Johnson syndrome4, toxic epidermal necrolysis4, drug reaction with eosinophilia and systemic symptoms (DRESS)4, acute generalised exanthemato us pustulosis (AGEP)4, dermatitis bullous4 | Generalised bullous fixed drug eruption (GBFDE), fixed drug eruption (FDE) | |
Musculoskel etal and connective tissue disorders | Arthralgia4 | Muscle spasms (leg cramps) | Myositis4 | |||
| Renal and urinary disorders | Blood creatinine increased, blood urea increased | Renal failure acute4, hypo-natraemia4 | Tubulointers titial nephritis4, nephrotic syndrome4, glomerulone phritis minimal lesion4 | |||
| Reproductiv e system and breast disorders | Menstrual disorder4 | Infertility female (female fertility decreased)3 | ||||
General disorders and administrati ve site | Influenza- like illness, oedema peripheral/ fluid | Face oedema, chest pain4 | ||||
| Adverse Drug Reaction Frequency | ||||||
| System organ class | 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) | Very rare (< 1/10,000) | Not known (cannot be estimated from available data) |
| conditions | retention | |||||
Injury, poisoning and procedural complicatio ns | Injury (accidental injury) | |||||
SGOT - serum glutamic oxaloacetic transaminase
SGPT - serum glutamic pyruvic transaminase
1 Adverse drug reactions that occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials). The adverse drug reactions listed above for the polyp prevention trials are only those that have been previously recognised in the post-marketing surveillance experience or have occurred more frequently than in the arthritis trials.
2 Furthermore, the following previously unknown adverse reactions occurred in polyp prevention trials, representing subjects treated with celecoxib 400 mg daily in 2 clinical trials of duration up to 3 years (the APC and PreSAP trials):
Common: angina pectoris, irritable bowel syndrome, nephrolithiasis, blood creatinine increased, benign prostatic hyperplasia, weight increased. Uncommon: helicobacter infection, herpes zoster, erysipelas, bronchopneumonia, labyrinthitis, gingival infection, lipoma, vitreous floaters, conjunctival haemorrhage, deep vein thrombosis, dysphonia, haemorrhoidal haemorrhage, frequent bowel movements, mouth ulceration, allergic dermatitis, ganglion, nocturia, vaginal haemorrhage, breast tenderness, lower limb fracture, blood sodium increased.
3 Women intending to become pregnant are excluded from all trials, thus consultation of the trial database for the frequency of this event was not reasonable. 4 Frequencies are based on cumulative meta-analysis with pooling of trials representing exposure in 38102 patients.
In final data (adjudicated) from the APC and PreSAP trials in patients treated with celecoxib 400 mg daily for up to 3 years (pooled data from both trials), the excess rate over placebo for myocardial infarction was 7.6 events per 1000 patients (uncommon) and there was no excess rate for stroke (types not differentiated) over placebo.
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:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
There is no clinical experience of overdose with Elyxyb. However, single doses up to 1200 mg and multiple doses up to 1200 mg celecoxib capsules twice daily have been administered to healthy subjects for nine days without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided e.g., by eliminating the gastric contents, clinical supervision and, if necessary, the institution of symptomatic treatment. Dialysis is unlikely to be an efficient method of medicinal product removal due to high protein binding.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-inflammatory and antirheumatic products, non-steroids, Coxibs, ATC code: M01AH01.
Mechanism of action
The mechanism of action by which celecoxib exerts therapeutic effects in migraine patients is not fully understood but may involve inhibition of prostaglandin synthesis, primarily via inhibition of COX-2.
Pharmacodynamic effects
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2 have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in humans but its relevance to ulcer healing has not been established.
Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides (e.g., thiazides, furosemide) but differs from arylamine sulfonamides (e.g., sulfamethoxizole and other sulfonamide antibiotics).
Platelets
In clinical trials using normal volunteers, celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time.
Because of its lack of platelet effects, celecoxib is not a substitute for acetylsalicylic acid for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib.
Fluid Retention
Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.
Clinical efficacy and safety
The efficacy of Elyxyb for the acute treatment of migraine with or without aura was demonstrated in two randomized, double-blind, placebo-controlled clinical trials [Study 1 (NCT03009019) and Study 2 (NCT03006276)].
In Study 1, patients were randomized to receive Elyxyb (n=316) or placebo (n=315); in Study 2, patients were also randomized to receive Elyxyb (n=311) or placebo (n=311). In both studies, patients were instructed to treat a migraine with moderate to severe pain intensity.
Patients enrolled in the trials were predominantly female (86%) and White (74%), with a mean age of 40.6 years (range 18 to 75 years).
The efficacy of Elyxyb was established by an effect on pain freedom at 2 hours post-dose and most bothersome symptom (MBS) freedom at 2 hours post-dose (co-primary endpoints). Pain freedom was defined as a reduction of moderate or severe headache pain to no pain, and MBS freedom was defined as the absence of the self-identified MBS (photophobia, phonophobia, or nausea). Among patients who selected a MBS, the most commonly selected MBS was photophobia (56%), followed by nausea (25%), and phonophobia (18%).
In both studies, the percentage of patients achieving headache pain freedom at 2 hours post-dose and MBS freedom at 2 hours post-dose was significantly greater among patients receiving Elyxyb, compared to those receiving placebo (see Table 3):
Table 3: Pain free rate at 2 hours and most bothersome symptom free rate at 2 hours post-dose in patients with migraine
| STUDY 1 | STUDY 2 |
| Celecoxib | Placebo | Celecoxib | Placebo | ||
| oral | (N=283) | oral | (N=282) | ||
| solution | solution | ||||
| (N=289) | (N=285) | ||||
| Headache Pain Freedom at 2 hours post-dose | |||||
| Reason for | Mild or none pain level at | 1 | 0 | 1 | 4 |
| exclusion | baseline | ||||
| from analysis | Missing pain level | 0 | 0 | 0 | 1 |
| baseline | |||||
| Results at 2 | Number of patients | 288 | 283 | 284 | 277 |
| hours post- | Proportion of | 32.0% | 24.3% | 35.3% | 21.4% |
| dose | responders* | ||||
| Odds-ratio [95% CI]* | 1.47 [1.01; | 2.00 [1.36; | |||
| 2.13] | 2.93] | ||||
| P-value* | 0.045 | <.001 | |||
| Absence of MBS at 2 hours post-dose | |||||
| Reason for | MBS at inclusion not | 36 | 41 | 43 | 36 |
| exclusion | present at pre-dose | ||||
| from analysis | Mild or none pain level at | 1 | 0 | 1 | 4 |
| baseline | |||||
| Missing screening MBS | 4 | 2 | 1 | 0 | |
| Results at 2 | Number of patients | 248 | 240 | 240 | 242 |
| hours post- | Proportion of | 57.7% | 45.0% | 57.3% | 45.5% |
| dose | responders* | ||||
| Odds-ratio [95% CI]* | 1.66 [1.16; | 1.61 [1.12; | |||
| 2.39] | 2.33] | ||||
| P-value* | 0.006 | 0.011 | |||
| * from a logistic regression with treatment group effect. | |||||
5.2 Pharmacokinetic properties
Absorption
Following administration of Elyxyb under fasting condition, the median time to peak plasma levels (Tmax) of celecoxib is about 0.75 hour. Dosing with food (high fat meal) delays absorption resulting in a Tmax of about 2 hours and decreases peak concentration (i.e., Cmax) approximately by 50% while total absorption (i.e., AUC) is unchanged. However, this has no significant influence on the effect of Elyxyb.
Distribution
In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. Celecoxib is not preferentially bound to red blood cells.
Biotransformation
Celecoxib metabolism is primarily mediated via cytochrome P450 2C9 (CYP2C9). Three metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human plasma i.e., a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate.
Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism.
In three separate single-dose studies, involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC0-24 increased by approximately 3-fold compared to normal metabolisers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3-1.0% among different ethnic groups. Patients who are known or suspected to be CYP2C9 poor metabolisers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution (see section 4.2).
Celecoxib metabolism is also mediated in a minor extent by CYP3A4 (< 25%) and CYP2D6, the latter being more noticeable in poor CYP2C9 metabolizers.
Elimination
Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged active substance recovered in the urine and feces. Following a single oral dose of radiolabeled active substance, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. Celecoxib elimination half -life (t1/2) is 8-12 hours.
Linearity/non-linearity
Linearity of celecoxib pharmacokinetics from Elyxyb has not been investigated.
Renal Impairment
There is little experience of celecoxib in renal impairment. The pharmacokinetics of Elyxyb has not been studied in patients with renal impairment and caution is advised when treating this patient population. The use of Elyxyb is contraindicated in patients with severe renal impairment.
Hepatic impairment
Compared to subjects with normal hepatic function, patients with hepatic impairment had an increased Cmax and AUC for celecoxib. The pharmacokinetics of Elyxyb has not been studied in patients with hepatic impairment and caution is advised when treating this patient population. Use of celecoxib in patients with severe hepatic impairment (serum albumin <25 g/l) have not been studied and Elyxyb is contraindicated in this patient group.
Elderly
Celecoxib exposure in elderly subjects (over 65 years old) following administration of Elyxyb has not been investigated. Caution is advised when treating this population.
5.3 Preclinical safety data
Celecoxib at oral doses ≥150 mg/kg/day in rabbits (approximately 7-fold human exposure at 120 mg daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 18-fold human exposure based on the AUC0-24 at 120 mg daily) throughout organogenesis. These effects are expected following inhibition of prostaglandin synthesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses, and reduced embryo/fetal survival.
Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was observed.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, mutagenicity, or carcinogenicity.
In a 2-year toxicity study an increase in nonadrenal thrombosis was observed in male rat at high doses.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lauroyl macrogolglycerides
Glycerol monocaprylate
Triglycerides medium-chain
Macrogolglycerol ricinoleate
Macrogolglycerol hydroxystearate
Propyl gallate
Levomenthol
Liquorice flavour, natural, liquid (monoammonium glycyrrhizinate dispersed in glycerol)
Sucralose
Acesulfame potassium
Glycerol
Ethanol, anhydrous
Peppermint flavour (contains propylene glycol, ethyl alcohol, natural and artificial flavour)
Bubble gum flavour (contains natural and artificial flavour)
Banana flavour (contains propylene glycol, artificial flavour)
Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
45 months.
After opening of the single-dose container: the medicinal product must be used immediately.
6.4 Special precautions for storage
Do not freeze.
6.5 Nature and contents of container
10 ml amber coloured glass, type III, bottle (single-dose container). The bottle is fitted with a high-density polyethylene child resistant closure with a Low Density Polyethylene inner liner.
The following pack sizes are available: 1, 2, 3, 6, 9, 12 bottles.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Ltd
410 Cambridge Science Park
Milton Road
Cambridge
CB4 0PE
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 08553/0778
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/05/2025
10 DATE OF REVISION OF THE TEXT
29/05/2026