Rhematology guidance: link to methotrexate-induced marrow suppression

Information below on:

Zostavax; Methotrexate (renal impairment, neutropaenia and sepsis; Leflunomide (serious drug toxicity)

ZOSTAVAX

As you know this is available for 70-79 year olds who are being  vaccinated in cohorts.

It is a live vaccine and should not, therefore, be given to patients who are any form of biologic therapy for their RA  (etanercept, infliximab, adalimumab, tocilizumab, abatacept, rituximab).  It is important to remember that these drugs are secondary care prescribed, and you should ensure that if calling patients in for vaccine that it is important to verify that they are not receiving any hospital drugs for their inflammatory arthritis.  I would recommend that patients receiving cyclophosphamide also be considered as falling into this group.

The Green Book advice on other immunosuppressives suggests that for lowish doses of methotrexate and azathioprine that the vaccine can still be offered.  The limit for azathioprine is 3mg/kg/day ( our upper limit of usage is usually 2.5 mg/kg) and methotrexate 0.4 mg/kg/week – this may mean that some light patients on methotrexate should perhaps not have the vaccine.  Practice nurses should thus be aware that they may have to weigh patients on methotrexate before deciding whether to immunise or not.

The dose of steroid considered “safe” is not clearly defined – the book simply states “low dose corticosteroid”.  I would normally consider that as 7.5 mg/day< of prednisolone.

As things stand, it doesn’t appear that we have the facility to immunise patients not within the planned cohorts prior to starting biologics.

If you do immunise any of our patients and see any subsequent shingles please could you let us know (as well as yellow card)?  

I hope that this makes things reasonably clear, but if in doubt don’t hesitate to ask – or ask your nurses to check with me or our specialist nurses.

METHOTREXATE

Renal Impairment, Neutropaenia and Sepsis

• Methotrexate is almost entirely excreted by filtration at the kidney.
• Any cause of reduced renal filtration (eg hypotension) increases the risk of haematological toxicity.
• In the acutely unwell rheumatology patient STOP methotrexate and monitor full blood count.
• If there is evidence of marrow suppression – particularly neutropaenia and thrombocytopaenia – give Folinic Acid rescue.
• Folinic acid resuce: 15 mg four times daily of IV Folinic Acid until marrow has recovered.  The advice of haematology should also be sought in relation to use of Filgrastin.  The usual protocol for neutropaenic sepsis should be followed for the patient with evidence of sepsis.
• Do not  simply give Folic Acid – Methotrexate inhibits the conversion of Folic Acid to Folinic Acid and to overcome toxicity the downstream product Folinic Acid must be given.

See following link for Guidance for all patients with neutropenic sepsis on Antimicrobial site:  http://intranet/resource.asp?uid=24654

LEFLUNOMIDE: Serious drug toxicity

Leflunomide is a disease modifying drug used in the treatment of rheumatoid and psoriatic arthritis.  Serious haematological and hepatic toxicity are not common but are well recognised.  

The drug has a half-life of 1-4 weeks.

For minor toxicity it may be reasonable to simply stop the drug, but on the understanding that it will take some time for the effect of the drug to reverse and that surveillance for the development of more serious toxicity must be undertaken, as minor cytopaenias or abnormalities of LFTs may worsen before they recover.  

For any severe reaction (or suspected severe reaction) a washout procedure should be performed (see below. 

Washout Procedure

If a washout procedure is required then either:

• Cholestyramine 8g three times daily
  • more palatable, lower risk of aspiration
  • Can be obtained from pharmacy, do not delay treatment
  • Can be given via NG tube OR
• Activated charcoal 50 g four times daily may be given.
  • Avoid if risk of aspiration

The recommended duration of washout drug is 11 days.

The duration of the washout procedure may be modified depending on severity of toxicity, response to treatment and in some cases the concentrations of active metabolite.

If toxicity is suspected take blood for

• FBC
• U&E and LFTs
• plus an additional tube plain gel (Brown) tube to be stored by the laboratory. 

The stored tube can be submitted to the manufacturer, Aventis, if necessary for measurement of levels.

Do not delay the commencement of the washout procedure in order to inform rheumatology, but please ensure that the rheumatologist is informed at the earliest opportunity.  If no rheumatology advice is available on site, the rheumatology service at the Western General Hospital in Edinburgh can usually provide additional verbal advice and support.