The primary efficacy endpoint was the sum of pain intensity difference SPID over 8 h assessed in the per-protocol population. The proportion of patients experiencing treatment-emergent adverse events was lower in the 50 Pain is the most common symptom for which patients seek medical attention, but often pain relief PAR is not achieved with the administration of a single drug [ 1 ].
Furthermore, studies have shown that many patients with acute pain will not achieve adequate analgesia [ 1 — 4 ]. Strategies to address this unmet medical need include multimodal analgesia, achieved via the use of multiple classes of pain-relieving drugs that have different mechanisms of action, with the aim of improving PAR [ 5 ].
A co-crystal is a solid form consisting of two or more dissociable components in a crystal lattice. Co-crystals containing more than one active pharmaceutical ingredient API represent unique molecular structures that offer a novel approach to polypharmacology [ 6 ].
Due to weak intermolecular interactions between drugs within the crystalline structure, API-API co-crystals have the potential for improved physicochemical properties compared with their constituent drugs, which may translate into clinical benefits. These may be apparent as enhanced solubility or dissolution characteristics, which in turn may improve pharmacokinetics PK compared with open or traditional fixed dose combinations FDCs [ 6 ]. Furthermore, co-crystals have relatively simple preparation methods and are not associated with many of the formulation issues that can be encountered with FDCs [ 7 ].
Co-crystal of tramadol—celecoxib CTC is a medical product in development that is based on a co-crystal molecule of two drugs with complementary mechanisms of action tramadol and celecoxib in a molecular ratio A mg dose of this co-crystal contains 44 mg of racemic tramadol hydrochloride rac -tramadol.
HCl and 56 mg of celecoxib. Tramadol is a centrally acting, weak mu-opioid receptor agonist and an inhibitor of the neuronal reuptake of noradrenaline and serotonin [ 8 ], and is indicated for the treatment of moderate to severe pain worldwide.
Celecoxib is a nonsteroidal anti-inflammatory drug NSAID that primarily acts via inhibition of cyclooxygenase In Europe and elsewhere, celecoxib is indicated and authorised for the treatment of chronic inflammatory conditions, such as osteoarthritis and rheumatoid arthritis, which are often painful [ 9 ].
In vitro analysis of a formulation of the co-crystal without additives ctc demonstrated intrinsic dissolution profiles for both tramadol and celecoxib from ctc that differed from tramadol and celecoxib administered individually or in open combination [ 10 ].
Preclinical pharmacological pain models have shown that the analgesic activity of ctc in suspension ctc susp is greater than the individual activities of tramadol and celecoxib and greater than the activity predicted by the sum of the individual components [ 11 ].
This increased analgesic activity is consistent with pharmacodynamic synergism i. Single- and multiple-dose phase I studies have compared the PK profile of CTC with that of the individual APIs given alone or in open combination in healthy volunteers.
These studies demonstrate that CTC exhibits several favourable changes in PK parameters relative to conventional dosage forms. Specifically, tramadol from CTC had a similar area under the concentration—time curve AUC , with a slightly delayed absorption, compared with tramadol alone or in combination with celecoxib.
This was associated with a lower maximum serum concentration C max , and a slightly prolonged time to reach C max T max [ 12 , 13 ]. These differences in PK parameters were consistent after single and multiple doses of treatment [ 12 , 13 ] and, together with the complementary molecular PAR mechanisms of each API, may have implications for both clinical efficacy and safety. Based on the preclinical efficacy synergism and human PK profile mentioned above, our hypothesis was that mg of CTC corresponding to 88 mg rac -tramadol.
HCl plus mg celecoxib has better efficacy relative to tramadol mg, and a similar safety profile, while lower doses of CTC have better efficacy and safety relative to tramadol mg, hence resulting in an improved overall benefit—risk ratio. Therefore, the primary objective of this clinical trial was to establish the effective dose among four doses of CTC for moderate to severe acute pain following oral surgery involving the extraction of two or more impacted third molars, requiring bone removal.
The secondary objectives were to assess the efficacy and safety of CTC. This was a dose-finding, double-blind, randomised, placebo- and active-controlled, parallel-group, phase II study a regulatory clinical trial: a clinical trial included in the clinical development programme for obtaining marketing authorization that was performed in nine Spanish hospitals. The study recruited patients with moderate to severe acute pain following oral surgery involving extraction of two or more impacted third molars, requiring bone removal.
The ethics committee of each study centre approved the study protocol. The study was conducted in agreement with the updated Declaration of Helsinki, the guidelines for Good Clinical Practice, and applicable Spanish regulatory requirements. Exclusion criteria included receipt of the following: any analgesic medication other than short-acting preoperative or intraoperative anaesthetic agents within 12 h before taking trial medication; any analgesic medication other than the study drug immediately after the oral surgical procedure; a long-acting NSAID within 3 days prior to dosing; any anti-depressive medication, selective serotonin reuptake inhibitors SSRIs e.
Patients were also excluded if they experienced any complications during surgery, had evidence of renal or hepatic dysfunction or peptic ulcer disease, or had a history of seizures or drug or alcohol abuse within 6 months of study entry.
All patients provided informed written consent. A computer-generated randomisation schedule was prepared at the start of the study and was balanced by the use of permuted blocks of six. Access to this schedule was limited to the staff who generated it and the staff who manufactured the products. To maintain the double-blind, each medication bottle was labelled with a medication code number and packaged with two identical capsules of study medication according to the randomisation sequence.
The investigator assigned medication code numbers to eligible patients in ascending sequential order. Treatment allocation information was contained in a sealed envelope that was only to be opened if needed in an emergency.
The study comprised three on-site visits and one telephone interview: screening visit 1 , oral surgery day 1, visit 2 , h post-surgery follow-up telephone interview day 2, visit 3 , and final examination day 7, visit 4. The acute pain model used in this study consisted of extraction of at least two impacted third molars at least one mandibular , requiring bone removal.
If only two impacted third molars were extracted, they were required to be ipsilateral and require bone removal at least one mandibular. After the molar extractions, the pain intensity PI of the patient was assessed on a mm VAS, scored by the patients themselves, at min intervals until a PI of 50 mm was reached, or up to a maximum of 4 h after extraction.
Patients who received study medication were required to remain at the study site for 12 h after randomisation i. At any time during the h observation period patients could take a supplementary analgesic medication rescue medication , but were encouraged to wait at least 1 h after taking the study medication and to wait until pain returned to baseline level.
Patients administered rescue medication discontinued the trial. Patients taking rescue medication were asked to remain at the study site for 8 h after randomisation.
Evaluation of analgesic efficacy included the assessment of PI, PAR, use of rescue medication, time to perceptible and meaningful PAR, and an overall assessment of the study medication. PI was assessed by mm VAS at time points min : 0 prior to taking the study medication , 10, 20, 30, 45, 60 1 h , 75, 90, , 2 h , , , , 3 h , , , , 4 h , , 5 h , , 6 h , 7 h , 8 h , 10 h , 12 h , and 24 h or until rescue medication was taken.
Completion of the VAS was observed by trained study staff. Stopwatches were used to assess time to PAR. Patients started timing upon intake of study medication and stopped one stopwatch at the onset of perceptible PAR and another upon achieving meaningful PAR. Alternatively, stopwatches were stopped at the end of the h observational period, at the time of withdrawal, or at the time of taking rescue medication whichever occurred first.
Patients also made an overall assessment of the study medication using a verbal rating scale excellent, very good, good, fair, poor at the time point the stopwatch was stopped. The primary efficacy endpoint was the sum of pain intensity difference SPID from 0 to 8 h.
Therefore, positive values correspond to an increase in pain, while negative values correspond to a decrease in pain. The secondary efficacy endpoints were SPID from 0 to 12 h, PID at each time point, PAR at 8 and 12 h, total pain relief TOTPAR from 0 to 8 h, TOTPAR from 0 to 12 h, overall assessment of the study medication, rescue medication rate of patients with intake of at least one dose of rescue medication up to 8 h and up to 12 h after study drug administration, and time to first intake of rescue medication , time to perceptible and meaningful PAR, and responder rates.
Evaluation of safety included the assessment of adverse events AEs spontaneously reported by the patients, safety laboratory tests, dental evaluation, general medical examination, vital signs pulse rate and blood pressure in sitting position, body temperature , and lead electrocardiogram ECG. A treatment-emergent AE TEAE was defined as an AE with onset on or after the first administration of study treatment, or an AE that worsened even if it was present before first administration.
Due to the exploratory nature of this study, no confirmatory hypothesis was set. Sample size was determined according to clinical, not statistical, criteria. For the primary efficacy analysis, 40 patients per treatment group were considered the minimum sample size necessary to properly evaluate the results of the study.
Therefore, to compensate for this expected loss, 60 patients per treatment group patients in total were recruited. The primary population for efficacy analysis was the per-protocol PP analysis set all randomised and treated patients who had no relevant protocol deviations, provided three or more valid VAS measurements within 8 h of study treatment, and did not take rescue medication during the first hour after study treatment.
The primary efficacy endpoint was analysed using an analysis of variance ANOVA model, including treatment and centre effects. Missing efficacy measurements in case of drop-outs or administration of rescue medication were imputed using the last observation carried forward LOCF method. The overall assessment of the study medication, response rates, and the number of patients requiring rescue medication were analysed using the Cochran—Mantel—Haenszel test stratified by centre, in order to detect any treatment differences.
The time to first intake of rescue medication, time to perceptible PAR, and time to meaningful PAR were analysed using Kaplan—Meier estimates and log-rank tests.
Time to response was analysed as time-to-event data, taking the first time at which the response criterion was reached by each patient. Safety variables were assessed in the safety analysis set all randomised patients who received study treatment and analysed descriptively. The low amniotic fluid started as early as 20 weeks of pregnancy.
There were 11 reports of low amniotic fluid levels during pregnancy and the fluid volume returned to normal after the NSAID was stopped. The medical literature has reported low amniotic fluid levels with use of NSAIDs for varying amounts of time, ranging from 48 hours to multiple weeks.
Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. NSAIDs may delay or prevent rupture of ovarian follicles which has been associated with reversible infertility in some women.
The withdrawal of NSAID therapy should be considered in women with difficulties conceiving or who are undergoing investigation of infertility. TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
Comments: -The US FDA recommends against the use of tramadol during breastfeeding due to risks of serious adverse reactions in breastfed infants; this drug is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Serious adverse reactions in breastfed infants may include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.
Newborns have limited capacity to metabolize the active 0-desmethyltramadol. Reanalysis of the data using a population pharmacokinetic model showed a maternal weight adjusted dose of 2. The amount of drug present in breast milk represents a maximum of 2. This drug can increase prolactin levels; however, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Comments: -Low levels of this drug are excreted in breastmilk and are not expected to cause adverse effects in breastfed infants. Limited data has shown this drug is excreted into human milk in low levels. No infant side effects were observed in these infants. Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum. Switch to: Professional Interactions.
These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Disclaimer: This content should not be considered complete and should not be used in place of a call or visit to a healthcare professional. Medication List Close Celebrex tramadol. Show 6 interactions. The following applies to the ingredients: Tramadol and Celecoxib found in Celebrex Celecoxib may increase the blood levels and effects of traMADol.
Your dose of celecoxib should be halved if you also take fluconazole. Ask your pharmacist for further advice. Read more detailed information about medicines that interaction with celecoxib here. Parenting Mental health Healthy eating Conditions Follow. Type keyword s to search. Celecoxib with other painkillers It's fine to take paracetamol with celecoxib. However, don't take the following painkillers while you're taking celecoxib, as this increases the risk of getting side effects on the stomach and intestines: painkilling doses of aspirin other related anti-inflammatory painkillers NSAIDs like ibuprofen or naproxen.
Other medicine interactions with celecoxib There may be an increased risk of bleeding if celecoxib is taken by people taking anti-blood-clotting medicines coumarin anticoagulants such as warfarin. Your kidney function should be monitored if you are taking any of these medicines in combination with celecoxib, particularly if you are elderly: ACE inhibitors, such as ramipril, enalapril angiotensin II antagonists, such as losartan ciclosporin diuretics, such as bendroflumethiazide, furosemide tacrolimus.
Celecoxib may also increase the blood levels of the following medicines and so could increase the risk of their side effects: antiarrhythmic medicines such as flecainide SSRI antidepressants such as citalopram, fluoxetine there may be an increased risk of bleeding in the gut if you take celecoxib with this type of antidepressant tricyclic antidepressants such as amitriptyline, clomipramine. There is a possibility that the following medicines may reduce the blood level of celecoxib and so could make it less effective: barbiturates carbamazepine rifampicin.
Read more detailed information about medicines that interaction with celecoxib here Related Story. This content is created and maintained by a third party, and imported onto this page to help users provide their email addresses.
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