Posted: 13 Feb 19
In this edition: • Gabapentinoids • Tapentadol • Tacrolimus Interactions • SGLT2 Inhibitors: side effects • Specific drug issues
In this edition:
Tapentadol is an opioid analgesic authorised for the relief of acute moderate to severe pain that can only be adequately managed with opioid analgesics in adults and children aged 2 years and older. Tapentadol is also indicated in adults for the management of severe chronic pain that can only be adequately managed with opioid analgesics.
Advice for healthcare professionals:
• As with all opioid medicines, tapentadol can induce seizures and should be prescribed with care in patients with a history of seizure disorders or epilepsy.
• Tapentadol may increase seizure risk in patients taking other medicines that lower seizure threshold, for example, antidepressants e.g. serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants and antipsychotics
• Serotonin syndrome has been reported when tapentadol is used in combination with serotoninergic antidepressants. Withdrawal of tapentadol, together with supportive symptomatic care, usually brings about a rapid improvement in serotonin syndrome.
• Report suspected adverse drug reactions, including those resulting from interactions between drugs, on a Yellow Card.
Safer Prescribing of Gabapentinoids (Gabapentin and Pregabalin)
Gabapentinoids i.e. pregabalin and gabapentin are widely used anti-epileptic drugs which are also licensed to treat neuropathic pain. Gapapentinoids are NOT licensed for non-neuropathic pain, nor is there any evidence to support this use. Following NHS Dumfries and Galloway formulary guidelines, they should only be used second or third line, after amitriptyline (or carbamazepine for trigeminal neuralgia). They are due to be reclassified as Schedule 3 controlled substances from April 2019.
Potent binding of pregabalin/gabapentin at the calcium channel results in a reduction in the release of excitatory molecules. In addition, gabapentinoids are thought to possess GABA-mimetic properties whilst possibly causing direct/indirect effects on the dopaminergic 'reward' system.
There has been a confirmed increase in the number of overdoses in Scotland associated with the misuse of gabapentinoids; this correlates with increased prescribing of these agents.
Care should be taken when prescribing gabapentinoids to those with a previous history of drug abuse and prescribers should monitor for signs of potential misuse or diversion, for example over-ordering or ad hoc requests for these drugs.
When starting gabapentinoids, titration of dose should be tailored to the patient, i.e. fast titration of gabapentin over 3 days is generally only suitable for healthy adults, slow titration with weekly dose increases is preferred for frail or elderly patients – refer to CKS or the individual SPC for recommended dose regimens.
Gabapentinoid treatment should be reviewed regularly, gradually withdrawing if ineffective. Neuropathic pain is difficult to treat and it is important to address patient expectations of pharmacological treatment, as its effectiveness is limited by many factors e.g. adverse effects. Consideration of non-pharmacological self-management is equally important when treating pain, including physical and psychological therapies, for example, exercise, yoga, tai chi, relaxation, CBT and mindfulness.
Further guidelines on gabapentinoid prescribing and management of chronic pain can be found at: https://www.therapeutics.scot.nhs.uk/pain/ and
Specific Drug Issues
Emollients: new information about risk of severe and fatal burns with paraffin-containing and paraffin-free emollients
Warnings about the risks of severe and fatal burns are being extended to all paraffin-based emollients regardless of paraffin concentration. Data suggests there is also a risk for paraffin-free emollients. Advise patients who use these products not to smoke or go near naked flames, and warn about the easy ignition of clothing, bedding, dressings, and other fabric that may have dried residue of an emollient product on them.
The manufacturer Mylan has ceased making the generic version of lofepramine resulting in supply issues. Lofepamine is more noradrenergic than other tricyclics, so there is no direct alternative. Possible alternatives include venlafaxine and duloxetine although these have enhanced serotonergic side effects. Clinicians are advised not to initiate lofepramine; this may also be an opportunity to review whether it is still required.
The Advisory Committee on Borderline Substances (ACBS) recently reviewed products VSL#3 and Vivomixx for continued inclusion in Part XV of the Drug Tariff. The Committee concluded that the evidence did not sufficiently demonstrate that these products are clinically effective. On this basis, both pr
There have been several incidences of people taking tacrolimus for immunosuppression associated with solid organ transplants being prescribed interacting drugs and presenting with tacrolimus toxicity.
Tacrolimus is a drug of narrow therapeutic range with significant interpatient variability. It is therefore subject to therapeutic drug monitoring, usually undertaken by specialist teams. Tacrolimus is affected by p-glycoprotein efflux and is metabolised via cytochrome P450-3A4; it is therefore susceptible to interactions with other drugs which affect these mechanisms.
Within General Practice, the most commonly prescribed interacting agents are listed below. For all these drugs, consider whether an alternative is appropriate and discuss with the specialist team before prescribing; they may advise an alternative, a temporary dose alteration and/or additional monitoring.
Macrolide antibiotics: Large increases in tacrolimus concentrations and nephro- toxicity have been reported with clarithromycin and erythromycin. Where possible, an alternative antibiotic (such as doxycycline) should be chosen.
Fluconazole: Fluconazole increases tacrolimus concentrations and increases the risk of nephrotoxicity. Use alternative topical products where possible and minimise the dose.
Diltiazem and Verapamil: Both these drugs inhibit P450-3A4 and large increases in tacrolimus levels have been reported in case studies.
Rifampicin: Rifampicin decreases the exposure to tacrolimus due to induction of P450-3A4 with the potential loss of its immunosuppressive effect.
In addition, tacrolimus has been associated with prolongation of the QTc interval and this should be considered when starting other medication known to prolong the QTc interval. Tacrolimus increases plasma potassium concentration and so potassium levels should be checked when starting other potassium-sparing drugs.
Note that tacrolimus should always be prescribed by brand products have been removed. In effect,
they should no longer be prescribed.
SGLT 2 inhibitors: Potential Life-threatening Side Effect
The marketing authorization holders of SGLT2 inhibitors (canagliflozin, empagliflozin, dapagliflozin and ertugliflozin) in conjunction with the EMA and MHRA have issued a warning relating to post-marketing cases of Fournier’s gangrene (necrotising fasciitis of the perineum) associated with this group of drugs (January 21st 2019). Clinicians are advised to be aware of patients presenting with pain, tenderness, erythema in the genital/perineal area accompanied by fever/malaise. Urogenital infections or perineal abscess may precede necrotising fasciitis.
Fournier’s gangrene is almost exclusively reported in men, however cases have been reported in women using SGLT2 inhibitors