Q.707.What are the adverse effects of this group of drugs?
KIDNEY TRANSPLANT
Renal transplantation-Allograft |
Q.707.What are the adverse effects of this group of drugs? 👎
A.Sirolimus (Siros) is
ass. é 🠞[leukopenia,
thrombocytopenia, anemia, hyperchlst., hyperTrG, Drr., etc.]. Hematologic effects: [Anemia,
thrombocytopenia & leukopenia.]. Anemia rep. in 27-57% of ptns. Combination of [MMF+
Siros]🠞🠝incidence of anemia. Thrombocytopenia obs.
in 13-30 % of ptn... Reductions in platelet
count are dose-related &
us. occur 9-10 d. after initiation of ttt . Normalization of platelet counts is seen é 2
w. of discontinuation
. Leukopenia, wch’s not dose-related, is evident é 2
w. of start of therapy & reversed upon discontinuation.
HUS/TMA: Rep. é Csp/Siros combin.: HUS was rep.
in 10 ptns. on Csp/Siros. Higher Csp
& Siros levels thn those ptns without HUS & discontinuation
of these ag.s🠞reversal of HUS in most cases. Incid.of HUS ws lower on a reg. of Csp/Siros comp. to controls on a Tcrol or
Csp. based reg. without Siros ☜
Single cohort study:
13 of 368 ptns dev. biopsy proven TMA. Incidence was highest é Csp/Sirs (20%)
comp. é other
reg., include Csp+MMF, tcrol+MMF & tcrol+ Siros. An incr. rate of hepatic a. thrombosis, graft loss
& death ws rep. in liver Tx. recip.. In two
multicenter, trials in de novo liver Tx. recip., use of Sirosin combin. é either Csp
or Tcrol ws
ass. é 🠝 rate of hepatic a. thrombosis . Furthermore, in one
phase II study, use of Siros+tcrol was associated é 🠝rate of death & graft loss.
Hyperlipidemia
& hyperchlst.:
dose-related effects of Siros due
to 🠟lipoprotein
lipase. Long-term
Rapa 🠞🠟gluc. metabism &
new onset D.M.. G.I.: S.E.: [constipation, Drr.,dyspepsia, n. & v.]. Mouth
sores, not rel. to herpes simplex, have been rep. é Siros oral solution & usually
dose-related. Oral
ulcers may occur é
combin. of [Siros+MMF] & sn
more frequently in steroid-avoidance protocols .
Respiratory
system: Progressive
interstitial pneumonitis has been observed. Increased risk for pneumonitis é late
switch to Siros &🠟R. function. Sms incl.:[SOB, dry cough,
fever & fatigue]. In
one rep.: radiographic & BAL🠞bronchiolitis
olibertans-organizing pn. & lymphocytic alveolitis. Complete
recovery occ. é 6
m. of Siros
withdrawal.
Kidney func.: Siros is minimally nephrotoxic if used
alone. However, combin. of Siros/Csp 🠞 synergistic nephrotoxicity
in animals &
humans, wch may be due to 🠝 R. & whole bld Csp levels and/or resultant
incr. in fibrogenic
cytokine TGF-B . Phase III clinical trials using Siros+Csp 🠞🠝 s. cr. &🠟GFR. These
effects were not obs. é Csp &
placebo or Aza controls. In addition, combin. of Siros/Tcrol, compared é Tcrol/MMF, is consistently ass. é dcrease R. func.in
several studies. R. func. should therefore be carefully
monitored in combin. thpy of [Siros
& CNI].There’s some
evidence that Siros 🠞DGF. Study:
of deceased or living donor kid. allog. recip., DGF ws signif.
more common é Rapa thn without this ag..
Proteinuria: Siros🠞proteinuria & G.N. (esp. FSGS): “Study”: Siros ws substitu-ted for a CNI, Prot
ws assessed prior to &
after
substitution. Comp. é baseline, Prot markedly incr. & reversed é
Siros
withdrawal. Ptns. converted to Siros, dev. Prot,
é 30 % develop FSGS. “Collapsing
FSGS” rep. é Siros, used é Kaposi's sarco-ma. Mech.
of Prot.: Siros🠞🠟tubuler
protein reabsorption, podocyte dysregulation
& over expression of vsc. endoth. growth f, 🠞🠝cell wall permeability 🠞collapsing FSGS.
Others: A unique form of cast nephropathy has been described é DGF & exten-sive tub. dge é use of [Tcrol +
Siros].
Casts were histologically indistinguishable
fr. those of myeloma Np.
ARF occur in ass. é myoglobinuria & myoglobulin-appearing casts hs
also bn rep. é Siros. Other rep. have noted 🠝 risk of DGF. Malignancy: PTLD is uncommon among those
given Siros &
Csp. There’s also some evidence that Siros may actually have anti-malignancy effects.
Teratogenicity/effects
in pregnancy & fertility:
Siros is C.I.
in pregnancy & its
use shd be discontinued at least 12 w. prior to attempted conception. Women post-Tx.
who wish to conceive shd be switched prior to conception fr. Siros
to Csp or Tcrol. Upon delivery, mother shd switch
back👉to her basal im/m. in view of potential
benefits of the newer ag.s to prevent late Ac. Rj. & CAN.
Siros🠞🠟spermatogenesis. Study: of 95 recep., total
sperm count was signif. lower é Siros. Ptn receiving Siros-based reg. hd signif.
decrease fathered pregnancy rate comp. é Siros-free regimen. So, men shd be
informed of risks/benefits of Siros.
Others: Siros has been associated é
leukocytoclastic vasculitis & postoperative wound complications.
There’s 🠝incidence of angioedema é ACEI+ either Siros or evrol.
Cutaneous: the most frequent
é
Siros:🠞[acne-like eruptions , scalp folliculitis , hidradenitis
suppurativa , edema , angioedema , aphthous ulceration &
epistaxis]. Pericardial
effusion
have been rep. é Siros therapy, in cardiac &
R. Tx. recip..
Evrol
has not bn comp.
to Siros in
direct trial, but in non-comp. trials, S.E. are similar. Comp. MMF to
evrol in
conjunction é Csp, most common S.E. é evrol:[peripheral edema,
constipation, H.T., nausea, anemia, UTI & hyperlipidemia].
Q.708. What drug interactions are known for these
medications?
A. As {Siros & evrol} are
substrates for cytochrome P450 3A, coadministration
of [Siros +
cytochrome P450 3A
inducers]
(anticonvulsants, rifampin, INH, St. John's wort) & é cytochrome P450 3A
inhibitors
(e.g. azole antifungals, non-DHP CCB,
macrolide A.B., grapefruit) 🠞Significant
interactions. òñ
Cyclosporin: Concurrent use of [Siros +Csp]🠞significantly higher peak/ trough levels & area under
conc.-time curve (AUC) if comp. to giving 4 h. apart. This ws shown in a single dose drug interaction
study in wch Siros
10 mg & Csp
300 mg (Neoral)
oral soft gelatin cp. given either simultaneously or 4 h. apart . When given together, Siros Cmax & AUC were
incr. by 116 % & 230
%, resp., relative to Siros alone. Whole-blood trough levels increased by 30 % é
concomitant dosing, and time to peak levels ws also shorter (1.8 vs 2.5 h.). By comp., when Siros given 4 h. after Csp,
Cmax & AUC were incr.
by 37 % & 80 %, resp., comp. to Siros alone. The
mean Csp
Cmax & AUC were not significant affected by Siros if
given concomitantly or 4
h. after Csp.
Because of these interactions & additive S.E. (hyperTrG, possibly HUS/TTP) é Csp, we prefer not to use
Csp + Siros. Nevertheless, when we do
use combin. of [Csp+
Siros],
it’s us. é setting of using Siros as either
rescue thpy or to help reduce Csp toxicity. So, it’s
recomm. : time of giving Siros be consistent é tht of Csp. Single-dose study in healthy subj.: Csp 175 mg incr. evrol AUC by 168 % (46-365 %) & Cmax
by 82 % if given é 2 mg evrol comp. é evrol
alone .
Tacrolimus: Alth. Siros & tcrol hv diff. mech. of action, they share
the same binding
protein (FKBP-12).
Initial in vitro rep.: antagonist effect betw. Siros & tcrol. However,
because of ubiquitous nature of FKBP-12, in vivo studies of Siros didn’t reveal competitive inhibition. tcrol doesn’t hv the same interactions é Siros as does Csp. In a cross-over study, simultaneous &
separate (4 h.) use of Siros & tcrol were compared. No signif. interactions
were found in pharmacokinetic parameters including AUC & Cmax .
A unique form of cast 🞜Np. described é DGF & extensive tub. damage é [tcrol + Siros]. Casts were histologically indistinguishable
fr. those of myeloma Np.
MMF: study of MMF
pharmacokinetic & either Siros
or Csp 🠞significant higher AUC
for MMF in Siros -ttted ptns if compared to Csp-ttt ptns . Similarly, mycophenolic
a. trough conc. were signif. higher in Siros ttted ptn.s. To avoid
toxicity, MMF dose reductions
is adviced if MMF/Siros
combination used.
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