tramadol (AVE-901) / Fortress - LARVOL DELTA

"All these PDUFA’s delivered on time for Opioids... but y’all can’t get a SINGLE application done, for Fortress Biotech IV Tramadol??" (@PJ_Weber)

PDUFA date

Avenue Therapeutics Announces that the FDA is Still Reviewing Its NDA Resubmission for IV Tramadol (Fortress Biotech Press Release) - "Avenue Therapeutics...today announced that the U.S. Food and Drug Administration ('FDA') was still reviewing its New Drug Application ('NDA') for IV tramadol and had not provided a decision regarding the NDA....An acknowledgement letter from the FDA in February 2021 stated that the Company’s resubmission of its NDA for IV tramadol was a complete, class 1 response to the Complete Response Letter ('CRL') dated October 9, 2020 and the resubmission had been assigned a Prescription Drug User Fee Act ('PDUFA') goal date of April 12, 2021."

FDA event • CNS Disorders • Pain

"$ATXI Avenue Therapeutics Announces that the FDA is Still Reviewing Its NDA Resubmission for IV Tramadol https://t.co/ou02cFKOqC" (@stock_titan)

NDA

Evaluate Safety of Tramadol in the Management of Postoperative Pain Following Surgery (clinicaltrials.gov) - P3; N=251; Completed; Sponsor: Avenue Therapeutics, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Pain

Avenue Therapeutics Provides Regulatory Update for IV Tramadol (Fortress Biotech Press Release) - "Avenue Therapeutics...today provided a regulatory update following receipt of the official meeting minutes from a November 2020 Type A meeting with the U.S. Food and Drug Administration (FDA) relating to a path forward for IV tramadol. Avenue had requested this Type A meeting to address a Complete Response Letter (CRL) it received from the FDA regarding the New Drug Application (NDA) for IV tramadol. Avenue intends to resubmit the NDA in February 2021."

FDA event • NDA • CNS Disorders • Pain

Avenue Therapeutics Receives Complete Response Letter from the FDA for IV Tramadol (GlobeNewswire) - "Avenue Therapeutics, Inc....today announced it has received a Complete Response Letter ('CRL') from the U.S. Food and Drug Administration ('FDA') regarding the Company’s New Drug Application ('NDA') for IV tramadol....The CRL stated that IV tramadol, intended to treat patients in acute pain who require an opioid, is not safe for the intended patient population....In addition, the CRL stated that the FDA requires an adequate terminal sterilization validation prior to NDA approval, which is planned for later this quarter."

FDA event • CNS Disorders • Pain

Avenue Therapeutics Plunges as FDA Rejects NDA for IV Tramadol (BioSpace) - "Shares of Avenue Therapeutics plunged more than 56% in premarket trading after the company announced the U.S. Food and Drug Administration (FDA) rejected its New Drug Application for intravenous tramadol over safety concerns."

FDA event • Stock price • CNS Disorders • Pain

Avenue Therapeutics Announces Publication of a Review of IV Tramadol (Fortress Biotech Press Release) - "Avenue Therapeutics, Inc....today announced that a publication entitled 'IV tramadol: A novel option for US patients with acute pain—A review of its pharmacokinetics, abuse potential and clinical safety record' has been published in the peer-reviewed journal, Journal of Opioid Management...This paper provides a review of the pharmacokinetics ('PK') of the IV tramadol dosing regimen intended for the U.S., its abuse potential as documented in the literature, its safety record in clinical practice outside the U.S."

Review • CNS Disorders • Pain

ACP, AAFP release new guideline for treatment of non-low back pain (Eurekalert) - "The American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) today released a new clinical guideline recommending that physicians treat acute pain from non-low back musculoskeletal injuries with topical NSAIDs, with or without menthol gel, as first-line therapy. The new, evidence-based, joint guideline was published today in Annals of Internal Medicine....The guideline also suggests that oral NSAIDS, acetaminophen, specific acupressure, or transcutaneous nerve stimulation are effective treatments and suggests against using opioids, including tramadol, except in cases of severe injury or intolerance of first-line therapies."

Clinical guideline • Pain

Publication highlights IV tramadol 50 mg demonstrated a statistically significant benefit (p-value < 0.05) over placebo for primary and all key secondary efficacy endpoints (Fortress Biotech Press Release) - P3, N=409; NCT03290378; Sponsor: Avenue Therapeutics, Inc.; "Avenue Therapeutics, Inc....today announced that the results from its Phase 3 study of IV tramadol in patients undergoing bunionectomy have been published in the peer-reviewed journal, Pain and Therapy....The study concluded that IV tramadol 50 mg was effective and well-tolerated as a treatment for postoperative pain following bunionectomy surgery, while IV tramadol 25 mg, although well-tolerated, was judged to be an ineffective dose for the treatment of pain in this setting."

P3 data • Pain

ADJUNCTS TO LOCAL ANAESTHESTICS: AN UPDATE (ESRA 2017) - "...Several adjuncts, including opioids, tramadol, clonidine and neostigmine, have been tested with single-shot regional techniques, but failed to achieve desired expectations.2, 4 In the last decade, two molecules have gained interest in regional anaesthesia, dexamethasone and dexmedetomidine...In summary, perineural dexamethasone at a dose of 8 mg prolongs duration of analgesia by a mean period of 8 hours, while dexmedetomidine at a dose of 50 to 100 µg increases this duration by a mean period of 4 hours. Both can be considered as efficacious adjuncts to local anaesthetics but clinicians should be aware that routes of administration represent off-label indications."

Retrospective data • Pain

Comparative efficacy of intravenous dexmedetomidine, clonidine, and tramadol in postanesthesia shivering. (PubMed) - J Anaesthesiol Clin Pharmacol - "All the three drugs were effective in preventing postoperative shivering. However, tramadol has been found to be more efficacious in preventing postoperative shivering."

Journal • Biosimilar • Depression • Gene Therapies • Pain

Opioid Prescribing Habits in Sickle Cell Disease: An International Survey of Providers (ASH 2018) - "...Overall, the top 5 most commonly prescribed medications for home pain management were; acetaminophen/paracetamol (98%), ibuprofen (88%), short acting morphine (55%), tramadol (52%) and oxycodone (48%). Non US physicians were more likely to prescribe acetaminophen/paracetamol (90%vs 68%, p<.05) and tramadol (69% vs 30%, p <.05), while US providers more likely to prescribe short acting morphine (64% vs 42%, p<.05), long acting morphine (60% vs 25%, p<.001), oxycodone (70% vs 15%, p<.001), oxycontin (44% vs 10%, p<.001) and dilaudid (64% vs 6%, p<.001)...However, identifying optimal home pain management strategies is also necessary to improve care in SCD. Finally, as more multinational studies of novel therapeutics are undertaken in SCD, it is important to note the significant geographic differences in medication prescribing both at home and in the hospital and to work to create multinational guidelines on outpatient management of VOC’s."

Biosimilar • Gene Therapies • Hematological Disorders • Pain

Avenue Therapeutics announces publications in peer-reviewed journals (GlobeNewswire) - "Avenue Therapeutics, Inc....today announced the following publications in peer-reviewed journals....The objective of this Phase 3 study was to evaluate the safety, tolerability and efficacy of IV tramadol 50 mg versus placebo in patients following abdominoplasty surgery...The results of the study demonstrated that IV tramadol was statistically superior to placebo and comparable to IV morphine for the primary and all key secondary efficacy outcomes....Safety study was a Phase 3, single-arm, open-label safety study...At the end of treatment, approximately 95% of the patients reported that study medication was good, very good, or excellent for controlling pain."

Clinical data • P3 data • Pain

A comparative study to evaluate ultrasound-guided transversus abdominis plane block versus ilioinguinal iliohypogastric nerve block for post-operative analgesia in adult patients undergoing inguinal hernia repair. (PubMed, Indian J Anaesth) - "...Seven patients (23.33%) in Group I and two (6.67%) in Group II required tramadol in first four hours...004). USG guided IIN/IHN block reduces the postoperative analgesic requirement compared to USG guided TAP block."

Clinical • Journal • Biosimilar • Pain

Comparision of Analgesic Efficacy of Tramadol Infusion Versus Tramadol Plus Ondansetron Infusion In Medical Intensive Care Unit. (PubMed, Indian J Crit Care Med) - "No nausea and vomiting were seen. We conclude that co-administration of tramadol and ondansetron can be practiced in medical ICU patients without any higher requirement in dosage of tramadol."

Clinical • Journal • Biosimilar • CNS Disorders • Depression • Pain

Comparison of continuous femoral nerve block (CFNB/SA) and continuous femoral nerve block with mini-dose spinal morphine (CFNB/SAMO) for postoperative analgesia after total knee arthroplasty (TKA): a randomized controlled study. (PubMed) - "Though in some patients CFNB was inadequate, a mini-dose of intrathecal morphine (0.035 mg) in addition to CFNB was found to be effective with minimal side effects."

Journal • Biosimilar • Pain

Evaluation of the route dependency of the pharmacokinetics and neuro-pharmacokinetics of tramadol and its main metabolites in rats. (PubMed) - Eur J Pharm Sci - "Drug targeting efficiency (DTE) values of tramadol after i.p. injection were more than unity for all scheduled time points. Considering the main analgesic effect of M1, it is hypothesized that both routes of administration may produce the same amount of analgesia."

Journal • Biosimilar • Pain

Postoperative Analgesic Efficacy of Bilateral Transversus Abdominis Plane Block in Patients Undergoing Midline Colorectal Surgeries Using Ropivacaine: A Randomized, Double-blind, Placebo-controlled Trial. (PubMed, Anesth Essays Res) - "TAP block produces effective and prolonged postoperative analgesia in patients undergoing midline colorectal surgery. It is a technically simple block to perform with a high margin of safety. It produces a considerable reduction in mean intravenous postoperative tramadol requirements, reduction in postoperative pain scores, and increased time to first request for further analgesia, both at rest and on movement."

Journal • Biosimilar • Pain

Herpes Simplex Virus (HSV) Encephalitis in a Frail Nursing Home Resident (AGS-AM 2017) - "A diagnosis was made of herpes zoster and he was started on Tramadol as needed for pain and Val acyclovir (1 g three times per day for 7 days. This is particularly important in patients with risk factors such as impaired cell mediated immunity. Prompt diagnosis with CSF evaluation and early antiviral therapy with intravenous acyclovir is particularly important as studies have shown that a delay of greater than two days between presentation to the hospital and initiation of acyclovir therapy is associated with poor outcomes"

Clinical • Alzheimer's Disease • Biosimilar • Chronic Kidney Disease • Diabetes • Gene Therapies • Immunology • Pain

Experimental Design to Optimize and Maximize Deterrence Capacity of Deterrent Blends (AAPS 2016) - "Methods: The optimum deterrent blend was determined using a simplex lattice design (Minitab® 17.1.0) with tramadol HCl used as a model drug of abuse. Experimental design was successfully employed to determine an optimized composition of deterrent agents to maximize drug binding in all common extraction solvents. Study showed that XCMC can be used in abuse-deterrent formulations as supplied, however clay and medicinal charcoal need to be coated to avoid undesirable binding under non-abuse conditions before they can be used in such formulations."

Clinical • Biosimilar • Pain

Comparative study of systemically and perineurally administered tramadol as an adjunct for supraclavicular brachial plexus block. (PubMed) - "In conclusion, the addition of tramadol to bupivacaine mixtures as an adjunct for supraclavicular brachial plexus block provide better postoperative analgesia for orthopedic upper extremity surgery in comparison to control or systemic tramadol group without any side effects."

Journal • Biosimilar • Pain

Efficacy of tramadol and butorphanol pretreatment in reducing pain on propofol injection: A placebo-controlled randomized study. (PubMed) - J Anaesthesiol Clin Pharmacol - "Pretreatment with both butorphanol and tramadol significantly reduced pain on propofol injection; however, they exhibited comparable efficacy among each other. Thus, either of these two drugs can be considered for pretreatment to reduce propofol injection pain."

Journal • Biosimilar • Pain

Influence of tramadol on acute thermal and mechanical cutaneous nociception in dogs. (PubMed) - Vet Anaesth Analg - "Tramadol was metabolized marginally to O-desmethyltramadol and failed to produce clinically relevant acute antinociception. Therefore, the use of tramadol for acute nociceptive pain is questionable in dogs."

Journal • Biosimilar • Demo Pain • Pain

Avenue Therapeutics Announces Presentation of IV Tramadol E-Posters (GlobeNewswire, Avenue Therapeutics) - "Avenue Therapeutics, Inc....today announced that two e-posters highlighting efficacy and safety results from its Phase 3 program are available for online viewing from the cancelled Annual Regional Anesthesiology and Acute Pain Medicine Meeting hosted by the American Society of Regional Anesthesia and Pain Medicine ('ASRA'). The meeting was originally scheduled to take place April 23-25, 2020 in San Francisco, CA and was cancelled due to COVID-19 concerns....'The results of these two studies indicate that IV tramadol may become a useful option in patients where exposure to conventional opioids is not desired.'"

P3 data • CNS Disorders • Infectious Disease • Pain