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Home , Tramadol

TRAMADOL Ultram (tramadol), Ultram ER (tramadol extended-release tablets); Conzip (tramadol extended-release capsules), Ultracet (tramadol / acetaminophen)

RATIONALE FOR INCLUSION IN PA PROGRAM

Background Tramadol is a centrally acting synthetic used to treat moderate to moderately severe chronic in adults. Along from analgesia, tramadol may produce symptoms including , somnolence, , , sweating and pruritus similar to . Tramadol has been shown to inhibit reuptake of and , as have some other opioid . Like with other opioids, all patients require monitoring for signs of abuse and , because use of opioid analgesic products carries the risk of addiction (1).

Regulatory Status FDA-approved indications: Ultram (tramadol) is indicated for the management of moderate to moderately severe pain in adults (1). Ultram ER and Conzip are opioid indicated for the management of moderate to moderately severe chronic pain in adults who require around-the- clock treatment of their pain for an extended period of time (2-3).

The development of a potentially life-threatening may occur with the use of tramadol products, including Ultram and Conzip, particularly with concomitant use of such as SSRIs, SNRIs, TCAs, MAOIs, and SRAs ();with drugs which impair metabolism of serotonin (including MAOIs); and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur with the recommended dose (1-3).

Possible illegal or illicit use should be considered when prescribing or dispensing Ultram in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses a significant risk to the patient that could result in overdose and death. Tramadol should be used in caution with patients with respiratory depression, head trauma, and when used in conjunction with or other drugs that cause central nervous system depression (1-4).

Ultram has a maximum dose of 400mg per day due to increased risk of adverse side effects. Ultram ER and Conzip have a maximum daily dose 300mg. Acute overdose may induce miosis, respiratory depression, , hypotonicity, and acidosis. Chronic side effects include fatigue,

Tramadol FEP Clinical Rationale

TRAMADOL Ultram (tramadol), Ultram ER (tramadol extended-release tablets); Conzip (tramadol extended-release capsules), Ultracet (tramadol / acetaminophen)

dizziness, , , visual disorders, nausea, , sweating, dry mouth, constipation, premature heartbeats, , dysphoria, and hallucinations Seizures have been reported in patients receiving tramadol. Studies have shown Tramadol-induced is dose dependent (5).

The safety and efficacy of Ultram ER and Conzip in patients under 18 years of age have not been established (2-3).

The safety and efficacy of Ultram in patients under 16 years of age have not been established (1).

CDC guidelines find that concurrent use of benzodiazepines and opioids might put patients at greater risk for potentially fatal overdose. Three studies of fatal overdose deaths found evidence of concurrent benzodiazepine use in 31%–61% of decedents (6)

CDC guidelines finds that given uncertain benefits and substantial risks that opioids should not be considered first-line or routine therapy for chronic pain (i.e., pain continuing or expected to continue longer than 3 months or past the time of normal tissue healing) outside of active cancer, palliative, and end-of-life care (6).

FDA warns that opioids can interact with and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the and cause toxicity (see Appendix 1 for list of drugs) (7).

The FDA is restricting the use of tramadol in children. Tramadol carries serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children (8).

Tramadol criteria was created with dosing above FDA limits in order to help existing patients that have been taking doses above the FDA limits to safely taper down their doses to the FDA appropriate levels. This will allow physicians to time to work with their patients in creating a custom taper that is safe and provides adequate pain control.

Tramadol FEP Clinical Rationale

TRAMADOL Ultram (tramadol), Ultram ER (tramadol extended-release tablets); Conzip (tramadol extended-release capsules), Ultracet (tramadol / acetaminophen)

Summary Tramadol is a centrally acting synthetic opioid analgesic used to treat moderate to moderately severe chronic pain in adults. Concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and SRAs (triptans) with tramadol may precipitate a potentially life-threatening condition called serotonin syndrome. The safety and efficacy of Ultram ER; Conzip in patients under 18 years of age have not been established. The safety and efficacy of Ultram in patients under 16 years of age has not been established. As with other opioids, all patients require monitoring for signs of abuse and addiction, as use of opioid analgesic products carries the risk of addiction even with appropriate medical care (1-4).

Prior approval is required to ensure the safe, clinically appropriate and cost effective use of Ultram, Ultram ER, and Conzip while maintaining optimal therapeutic outcomes.

References 1. Ultram [package insert]. Titusville, NJ: , Inc.; September 2017. 2. Ultram ER [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; August 2017. 3. Conzip [package insert]. Sayreville, NJ: Vertical Pharmaceuticals LLC. September 2017. 4. Boostani R, Derakhshan S, Tramadol induced seizure: 3 year study. Caspian Journal of Internal Medicine. 2012; 3(3): 484-487. 5. Dowell D, Haegerich T, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain. CDC Guidelines 2016 6. FDA Safety Release. FDA Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. December 11, 2017. 7. FDA Safety Release. FDA Drug Safety Communication: FDA restricts use of prescription pain and cough medicines and tramadol pain medicines in children; recommends against use in women. December 11, 2017.

Tramadol FEP Clinical Rationale

TRAMADOL Ultram (tramadol), Ultram ER (tramadol extended-release tablets); Conzip (tramadol extended-release capsules), Ultracet (tramadol / acetaminophen)

Appendix 1 - List of Serotonergic

Selective Serotonin Reuptake Inhibitors (SSRIs) Paxil, Paxil CR, Pexeva, Brisdelle Luvox, Luvox CR Prozac, Prozac Weekly, Sarafem, Selfemra, Symbyax Zoloft Celexa Lexapro

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Effexor XR Pristiq, Khedezla Cymbalta Savella

Tricyclic Antidepressants (TCAs) No brand name currently marketed Norpramin Anafranil Tofranil, Tofranil PM Pamelor, Aventyl Vivactil Zonalon, Silenor Surmontil

Monoamine Oxidase Inhibitors (MAOIs) isocarboxazid Marplan phenelzine Nardil Emsam, Eldepryl, Zelapar tranylcypromine Parnate

Other Psychiatric Medicines No brand name currently marketed No brand name currently marketed No brand name currently marketed Oleptro No brand name currently marketed Viibryd Remeron, Remeron Soltab

Tramadol FEP Clinical Rationale

TRAMADOL Ultram (tramadol), Ultram ER (tramadol extended-release tablets); Conzip (tramadol extended-release capsules), Ultracet (tramadol / acetaminophen)

llthium Lithobid

Migraine Medicines Axert Frova Amerge Maxalt, Maxalt-MLT Imitrex, Imitrex Statdose, Alsuma, Sumavel Dosepro, Zecuity, Treximet Zomig, Zomig-ZMT

Antiemetics Zofran, Zofran ODT, Zuplenz Kytril, Sancuso Anzemet Aloxi

Other Serotonergic Medicines Bromfed-DM, Delsym, Mucinex DM, Nuedexta linezolid Zyvox Amrix St. John’s wort

Tramadol FEP Clinical Rationale