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 castž 🞜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.