3. Introduction
Cytotoxic drugs (Anti-neoplastics) –
Drugs that contain chemicals toxic to cells,
preventing their replication or growth inhibit or
prevent the function of cells
Primary role - Cancer Rx
3
4. Others –
Rheumatoid diseases, steroid-resistant
muscle conditions, severe dermatologic diseases
Many normal cells are damaged along
with cancer cells.
Myelosuppression, mucosal irritation,
carcinogenesis, teratogenesis etc
4
7. Alkylating agents
Act independently of the cell cycle
Direct damage to DNA
- Alkylation:
(N7) guanine in DNA: main target
↓
Cross linking, Abnormal base pairing
7
8. Bifunctional agents:
Intra- & interchain cross-linking
↓
Interferes with replication
& transcription
↓
Cell death
(Apoptosis)
8
9. Cyclophosphamide
Derived from nitrogen mustard (Mechlorethamine).
1st synthesized in 1957
Effective cytotoxic & immunosuppressive
agent - Antineoplastic
Highest T.I.
9
10. 10
• Dermat –
Immunosuppressive &
“steroid-sparing’ agent.
Oral & IV preparations
• Cytotoxic effects
independent of the
cell cycle.
11. Cyclophosphamide
B cells > T Cells
Suppressor T cells > Helper T cells
(Rx of Advanced cutaneous T cell lymphoma & as
Immunosuppressant)
Resistance
- ↓ cellular penetration
- improved DNA repair
- ↑ drug metabolism.
11
13. Therapeutic guidelines -
• AntiCa dose: 100mg/𝒎 𝟐/day oral
500mg/𝒎 𝟐
/day IV
• Dermatological dose
- 2-3 mg/kg/day in divided doses,
4-6 wk delay in onset of action.
• IV pulse therapy:
- 0.5-1 g along with Dexamethasone(100mg)
- very severe or refractory Pemphigus .
(fewer A/E than daily oral dosing)
13
14. Adverse effects
Haemorrhagic cystitis & Bladder Ca –
• 5-41% of patients
• Metabolite responsible – Acrolein
• Rx: MESNA
- conjugates acrolein in the bladder & ↓ irritation.
- Orally or IV.
- prolonged or high-dose Rx with Cyclophosphamide
- ↑ fluid intake
• Unchecked bladder toxicity Bladder Ca
14
20. A/E of Alkylating agents
1. Bone marrow suppression
• Dose-limiting a/e
• Leukopenia &/or thrombocytopenia
(Less common with Cyclophosphamide)
• Opportunistic infections
(P.jiroveci, fungal infs,
reactivation of Hep B)
20
21. 2. Carcinogenesis
• Non Hodgkin’s Lymphoma, leukemia & SCC
• Cyclophosphamide - high doses for long
durations
• Chlorambucil - lower doses & for shorter
duration
3. Gastrointestinal
• Mucosal toxicity Nausea, Vomiting
• Rx: Ondansetron & Dexamethasone.
21
23. Contraindications -
Absolute –
1) Drug allergy
2) Depressed bone marrow function
3) Pregnancy & lactation
Relative –
1) Active infection
2) Impaired hepatic & renal function
3) Seizure/Mood disorder (Chlorambucil)
23
24. Antimetabolites
Drugs that interfere with >/=1 enzymes or
their reactions necessary for DNA synthesis.
Act as substitutes to actual metabolites used in
normal metabolism
Inhibit cell division @ S phase of cell cycle
24
28. TG -
Starting dose - 5-7.5mg/wk
(max of 15mg/wk)
↑ gradually to 10-25mg/wk if needed
2 methods of weekly administration:
28
Once wkly regimen
(10-25mg)
3 divided doses/wk
(2.5mg each orally
over a 24 hr period)
• Max – 30mg/wk
32. 5-Fluorouracil (5-FU)
• 1st demonstrated in 1950.
Since then - IV chemotherapeutic agent in Rx
of various Ca.
• 1963 – Used as topical agent
(20% FU used to treat extensive Actinic
keratosis.
• Structure –
analogue of Uracil.
32
38. PK -
• Well absorbed orally
• Metabolized to 6-mp
• Inactivation – Xanthine oxidase
(dose ↓ when given with allopurinol)
TG –
• Starting dose: 1-2 mg/kg/day.
• Started early (requires 6-8 wks for effect)
38
39. D/I -
Others:
XO inhibitors: Allopurinol
(most important)
ACEIs
Folate antagonists
• ↑ myelosuppressive action of Azathioprine.
39
55. References -
1) Comprehensive Dermatologic Drug Therapy –
Stephanie E. Wolverton
2) Pharmacological Basis of Therapeutics –
Goodman & Gilman
3) Basic & Clinical Pharmacology –
Katzung & Trevor
3) Rang & Dale’s Pharmacology
55
Hinweis der Redaktion
Cytotoxic drugs (sometimes known as antineoplastics) describe a group of medicines that contain chemicals which are toxic to cells, preventing their replication or growth, thereby inhibit or prevent the function of cells
Cytotoxic drugs are primarily used to treat cancer, frequently as part of a chemotherapy regime. (Cytotoxic drugs can prevent the rapid growth and division of cancer cells) Recently, their uses have expanded to treat certain skin conditions (e.g., psoriasis), rheumatoid and juvenile rheumatoid arthritis, and steroid-resistant muscle conditions.
these medications are used in severe dermatologic diseases, in which previously corticosteroids were the only effective treatment available. Cytotoxic drugs have the potential to improve survival and to decrease morbidity, by reducing the requirement for corticosteroid therapy.
They can also affect the growth of other quick dividing cells in the body, like hair follicles and the lining of the digestive system. As a result of the treatment, many normal cells are damaged along with the cancer cells.
In dermatology cytotoxic agents are used to treat severe &/or refractory skin diseases – recalcitrant psoriasis, mycosis fungoides, connective tissue disease, vasculitis, immunobullous disorders & neutrophilic dermatoses, to name a few.
When treating severe skin disease, these agents are typically used at immunomodulatory doses. The clinician must be aware of the risks of carcinogenesis, teratorgenesis & myelosuppression with increased potential of infection with these agents.
These CAs can damage rapidly dividing normal cells, this depresses both cellular as well as humoral immunity; this can be both beneficial as well as harmful; beneficial in Rx of various AIDs,
Harmful bcos likely to depress bone marrow, impair healing and depress growth , cause hair loss & GI disturbances. On prolonged use - depression of gametogenesis (particularly in men), leading to sterility, and an increased risk of acute non-lymphocytic leukaemia and other malignancies.
Cas may be divided into 2 general classes –
Antimetabolites
Alkylating agents.
Cytotoxic agents & cell cycle
Cas modulate the behavior of cells through inhibition of growth & development. Knowledge of ‘cell cycle’ is necessary to understand the mechanism of action of mny of these drugs.
(pic)
In brief the cell cycle begins with the G1 phase, which is directed towards preparing the cell for DNA synthesis.
The subsequent S phase is devoted to DNA synthesis. At the end of S phase. G2 phase or interphase occurs, f/b M phase of actual cell division. Some cells of the body may enter a G0 (resting) phase of indeterminate length, awaiting a stimulus or conditions upon which to re-enter the cell cycle.
Alkylating agents
Exert their effect by direct damage to DNA, usually through physicochemical interactions such as alkylation by forming covalent bonds with the nucleophilic centres of DNA. Leads to DNA cross linking, abnormal base pair formation, imidazole ring cleavage ultimately leading to cell death.
These agents act independently of the cell cycle. The nitrogen at position 7 (N7) of guanine, being strongly nucleophilic, is probably the main molecular target for alkylation in DNA, other bases are also alkylated albeit to lesser degrees.
Most of the cytotoxic anticancer alkylating agents are bifunctional, can cause intra- or interchain cross-linking (Fig. 55.3). This interferes not only with transcription, but also with replication cell death (apoptosis) which is probably the critical effect of anticancer alkylating agents. This forms a basis for their therapeutic and toxic properties
Cyclophosphamide
Is an alkylating agent derived from nitrogen mustard (mechlorethamine*). Was 1st synthesized by Arnold & Bourseaux in 1957. the most commonly used alkylating agent as it has the highest T.I. Effective cytotoxic & immunosuppressive agent.
While in oncology C is used as an antineoplastic agent, in dermatology it is used as an immunosuppressive & “steroid-sparing’ agent. Both oral & iv prepns of C are used in Dermat.
* Mechlorethamine was the first clinically used nitrogen mustard. Rarely used in clinical practise.
MOA
Cytotoxic effects are independent of the cell cycle.
. The primary metabolites of C are responsible for (a carbonium ion being the reactive intermediate)
C has greater effect on B Ls than T Ls & a greater effect on suppressor T cells than helper T cells. (1 of its uses – Rx of advanced cut T cell lymphoma & can also be used as an immunosuppressant)
Resistance to C may occur d/t decreased cellular penetration, improved DNA repair or increased drug metabolism.
PK –
Usually given orally Cyclophosphamide is well absorbed orally, has high B.A. (~75%). Maximal concentrations in plasma are achieved 1 hour after oral administration & plasma T1/2 is ~7hrs
It is inactive until metabolized in the liver by P450 enzyme Cyt P-450 system, the prodrug is converted to 4-hydroxyC which exists in equilibrium with Aldophosphamide. Both 4-HC & A readily diffuse into cells, where A is cleaved intracellulary to phosphoramide mustard, an active metabolite which is responsible for antitumor effects while acrolein causes hemorrhagic cystitis often seen during therapy with cyclophosphamide. A can also be converted to an inactive metabolite –carboxyphosphamide & C is excreted in the urine mainly in this form (30-60%), only <20% of unmetabolized drug is excreted in urine.
The usual oral dosage is 2-3 mg/kg/day in divided doses, there is often a 4-6 wk delay in onset of action.
Another form of cyclophosphamide administration is iv pulse therapy of 0.5-1 g along with dexamethasone.27 This combination regimen is indicated in cases of very severe pemphigus or those cases refractory to usual therapy. May be a/w fewer a/e than daily oral dosing.
The cyclophosphamide-dexamethasone pulse therapy regimen would be implemented with intervals of 21 or 28 days. On the first day sequential cyclophosphamide-dexamethasone pulses are done. On the second and third days, only dexamethasone is used. Cyclophosphamide (1000mg or 10-15 mg/kg) is diluted in 500ml of GS5%, infusing it in 3 to 4 hours. Dexamethasone 100mg (2ml ampoule with 25 mg - 4 ampoules) is diluted in 250 ml of GS5%, infusing it in 3 to 4 hours.
pulse therapy with cyclophosphamide guarantees better results than daily doses of the drug, and it also reduces the occurrence of side effects.(Dexa is known to increase the met of Cy)
A/E
H’gic cystitis & bladder Ca –
Bladder toxicity is probably the single most widely recognized consequence of C use (5-41% of pts Rx with C). Metabolite responsible – acrolein
Can be prevented by administering a scavenging thiol agent MESNA (sodium-2-mercaptoethane sulfonate). Acts by conjugating acrolein in the bladder & reduces irritation. Admin orally or iv.
MESNA is typically recommended for those taking oral C for prolonged periods &/or at a particularly high dose.
In addition increased fluid intake can also reduce bladder comlications.
Unchecked bladder toxicity can markedly increase the risk of TCC of bladder. May arise many yrs, or even decades after Rx & continued monitoring of lower urinary tract is indicated in all patients who have used the drug.
D/I
Chlorambucil
another alkylating agent also derived from N mustard. In derma Cl is used more rarely than C
MOA –
Same as that of C: cell-cycle indepedent alkylating agent that exerts its effects through direct damage to DNA via cross-linking.
PK-
Given orally, with 87% B.A., but food reduces its b.a. by 10-20%. Highly protein-bound to alb (99%), has plasma T1/2 of approx. 1.5 hrs.
Although the drug is metabolized by the liver, unlike C it doesn’t require activation in the liver, but more importantly the drug metabolism doesn’t yield acrolein & no risk of h’gic cystitis. (adv over C)
Therapeutic guidelines –
Supplied as 2mg tab.
Recommended dose: 0.05-0.2 mg/kg daily. For cut ds doses usually remains near the lower end of this range. Typically inductive doses range from 4-10 mg/day, & maintenance doses are often 2-4 mg/day od. Results are usually expected with 3-6 wks of continued use.
C
1. Bone marrow suppression –
Can cause acute myelosuppression with resultant leukopenia &/or thrombocytopenia (latter is less with C than other drugs)
Dose-limiting a/e immunosuppression – can be reversible @ usual doses, but opportunistic infs can occur (P.jiroveci, fungal infs, reactivation of Hep B)
Because of these 2 a/e C is used only in the most severe, recalcitrant dermatologcal ds.
2. Carcinogenesis –
In +n to risk of bladder Ca, C is also a/w devp of other Ca – NHL, leukemia & SCC. Following exposure to high doses for extended durations. However when used for Rx of most skin disorders there is probably a lesser risk d/t use of lesser doses & shorter courses.
3. GI –
M/c – N & V (can affect 70-90% of users). d/t mucosal toxicity. May require co-admn of ondansetron & dexamethasone. Addition of aprepitant mat provide even better anti-emetic action.
[Box 17-8]
4. Effects on skin –
Alopecia (usually reversible, can be permanent
..
Rarely urticarial & SJS.
5. Finally, all alkylating agents have toxic effects on the male and female reproductive systems, causing an often permanent amenorrhea, particularly in perimenopausal women, and an irreversible azoospermia in men.
Cl
A/E –
Gen a/e –
Altho Cl is relatively less toxic form of N. mustard, common a/e are similar to those of C – N & V, azoospermia, amenorrhoea, pul fibrosis, seizures, derma s/e & hepatotoxicity. In particular, the epileptogenic potential & mood alterations attributed to Cl are significant.
Carcinogenesis –
Admn of Cl particularly in transplant pts, Ca pts & pts with significant conn t. ds, a/w increased risk of secondary malignancies, particularly leukemia & SCC. Even seen with lower doses & for shorter duration of Rx as in dermatological ds. Therfore approp pt counselling & consent is indicated.
C
C/I (table)
Antimetabolites
Antimetabolites are drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis. They affect DNA synthesis by acting as a substitute to the actual metabolites that would be used in the normal metabolism (for example antifolates interfere with the use of folic acid). Thus they are more active during the S phase
Classifn –
Ams commonly used in derma –
Mtx, Aza, mycophenolate mofetil, top 5-FU, thioguanine & HU
Methotrexate
Folate antagonist & anti-folate, is the most commonly used antimetabolite in derma.
In the 1940s, during tests to determine the effect of folic acid on acute leukemia in children, the antifolate (methotrexate) was synthesized. It was later approved by the FDA as an oncologic drug in 1953.
Structurally Mtx is a chemical analogue of FA (consists of 3 elements - …)
MOA –
Potent comp antagonist of DHFR enz.
Folates are actively taken up into cells by folate transport system, where they are converted to polyglutamates. In order to act as coenzymes, folates must be reduced to tetrahydrofolate (FH4). This two-step reaction is catalysed by dihydrofolate reductase, which converts the substrate first to dihydrofolate (FH2), then to FH4 (Fig. 55.6). FH4 functions as an essential co-factor in the synthesis of purines, pyridines DNA. Methotrexate has a higher affinity than FH2 for dihydrofolate reductase and thus inhibits the enzyme (Fig. 55.6), depleting intracellular FH4.
Thus the overall effect of MTX is inhibition of cell division, specifically in the S phase of cell cycle. This is the basis for its immunosuppressive & cytotoxic effects. However its anti-inflammatory effect is not known to be d/t inhibition of DHFR. It is predom mediated by adenosine
PK-
Methotrexate is usually given orally (as it is readily absorbed from GIT) but but larger doses are absorbed incompletely and are routinely administered intravenously, can also be given intramuscularly or intrathecally
The drug has low lipid solubility and thus does not readily cross the blood–brain barrier. It is, however, actively taken up into cells and is metabolised to polyglutamate derivatives, which are retained in the cell for weeks (or even months in some cases)
Renal excretion is the main route of elimination; Up to 90% of a given dose is excreted unchanged in the urine within 48 hours.
Metabolism of methotrexate in humans usually is minimal. After high doses, however, metabolites are readily detectable; these include 7-hydroxy-methotrexate, which is potentially nephrotoxic. Therefore dose-adjustment is required in pts with renal insuffieciency.
The biologic effects of MTX can be reversed by administration of the reduced folate leucovorin (5-formyltetrahydrofolate) or by l-leucovorin, which is the active enantiomer. Leucovorin rescue (100mg/m2) is used in conjunction with highdose MTX therapy to rescue normal cells from undue toxicity
Therapeutic guidelines –
A usual starting dose of Mtx Rx is 5-7.5mg/wk (max of 15mg/wk) this dosage may be increased gradually to 10-25mg/wk if needed.
There are 2 methods of weekly administration: once wkly regimen (10-25mg) or 3 divided doses (2.5mg each) orally over a 24 hr period each wk. total weekly dose should not exceed 30mg. In gen, patients with psoriasis are able to achieve benefits at 10-15 mg/wk.
When max benefit is reached mtx may be tapered by 2.5mg/wk. in c/o im mtx
D/I –
Methotrexate should never be co-administered with trimethoprim–sulfamethoxazole, probenecid, salicylates, or other drugs that can compete with it for protein binding and thereby raise plasma concentrations to levels that may result in bone marrow suppression.
5-FU
Another anti-metabolite. 1st demo in 1950, since then widely used as an IV chemotherapeutic agent in Rx of various Ca. its use as top agent began in 1963 when 20% FU was used to treat pts with extensive Actinic keratosis.
Str – it’s a strl analogue of uracil with a fluorine atom at the C5 position instead of H.
MOA –
5-Fluorouracil (5-FU) is inactive in its parent form, converted to its active metabolite 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) by a series of enz reactions(ribosylation & phosphorylation). It forms a covalent bond with thymidylate synthetase & hence prevents conversion of DUMP to DTMP, thereby inhibiting DNA synthesis (like Mtx), also its metabolites are misincorporated into RNA & disrupt RNA synthesis as well.
PK-
5-FU is administered parenterally, because absorption after oral ingestion of the drug is unpredictable and incomplete.
However in dermat ds – top application preferred, bcos of 15-75x greater degree of sys absorption.
Intralesional inj of 5-FU have also been used for sm ds – keratoacanthomas, warts etc
Metabolism – after it enters skin 5-FU is converted to several active metabolites (FdUMP, FdUTP, FUTP). A key enzyme in the metabolic pathway is dihydropyrimidine DH (DPD) which converts 5-FU to dihydrofluorouracil (DHFU).
Therapeutic guidelines –
Available as 1, 2 & 5% solutions (applied twice daily) & 0.5, 1 & 5% creams (applied od). Treatment duration: 2-8 wks.
Azathioprine
Azathioprine (IMURAN, others) is a purine antimetabolite. It is an imidazolyl derivative of 6-mercaptopurine,
Azathioprine was first introduced as an immunosuppressive agent in 1961, helping to make allogeneic kidney transplantation possible.
During 1960s-1970s it became the DOC for organ transplantation. Apart from immunosuppression it has also got anti-inflammatory properties.
In dermatological practice it is used off-label as a steroid-sparing agent for auto-immune & inflammatory dermatoses.
MOA-
A metabolized to 6-thioguanine metabolites which are structurally similar to endo purines (adenine & guanine). Exact mech by which these purine analogs lead to immunosuppression & anti-inflammatory effects is not known. However d/t strl similarity 6-thioguanine may get incorporated into DNA & RNA inhibiting purine synthesis & cell division. Also A is known to depress T-cell mediated function & B-cell mediated Ab production which is of central importance in immunobullous dermatoses.
PK-
Azathioprine is well absorbed from the gastrointestinal tract, The t1/2 of azathioprine is ~10 minutes, while that of its metabolite, 6-mercaptopurine, is ~1 hour.
metabolized primarily to mercaptopurine. Xanthine oxidase converts much of the active material to 6-thiouric acid prior to excretion in the urine
Since much of the drug’s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol (see Chapters 36 and 54) for control of hyperuricemia should have the dose of azathioprine reduced to onefourth to one-third the usual amount to prevent excessive toxicity
Therapeutic guidelines –
The usual starting dosage is 1-2 mg/kg/day. Because it generally takes 6-8 weeks to achieve therapeutic effect, azathioprine often is started early in the course of disease management.
D/I –
Most imp d/I occurs between A & allopurinol.
Other drugs which increase myelosuppressive property of Az –
Mycophenolate mofetil
Is a semisynthetic derivative of Mycophenolic acid which is a product obtained from the fungus Penicillium
An antimetabolite
Str-
2-morpholinoethyl ester of mycophenolic acid (MPA).
MOA –
Basically a purine synthesis inhibitor. MMF is a prodrug that is rapidly hydrolyzed to the active drug, MPA, a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an important enzyme in the de novo pathway of guanine nucleotide synthesis. B and T lymphocytes are highly dependent on this pathway for cell proliferation. Therefore MMF inhibits proliferation of T & B Ls, & reduced the production of cytotoxic T cells.
PK-
Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Approx 97% of MPA is bound to alb.
MPA is then inactivated by glucuronidation. T1/2 - ~16-18 hrs. Elimination – urine as inactive glucuronide.
Therapeutic guidelines-
MMF is used increasingly to Rx inflamm & AIDs in derma in dosages ranging from 1-2g/day orally.
Hydroxyurea
Was 1st synthesized by Dressler & Stein in 1869. over time it has been used to treat a variety of conditions m/cly heatological malignancies & SCA. In derma, HU is used mainly in psoriasis.
MOA-
.
Impairs DNA synthesis through inhibition of ribonucleotide diP reductase, an enz that reduces nucleotides to deoxynucleotides. This limits the supply of DNA bases available for synthesis, thereby resulting in strand breakage & cell death.
HU is also a radiation sensitizer, preventing cells from repairing damage d/t ultraviolet or ionizing radiation.
Lastly through hypomethylation HU alters gene expression. It is though that this effect may lead to improved differentiation in psoriatic skin.
HU is most effective in cells with a high proliferation index, as it acts upon cells entering S phase of the cell cycle, preferentially concentrated within leucocytes
TG –
Available as 500mg capsules. Typical dose range from 1-2g daily, usually as divided dose of 20-30mg/kg daily. Doses above 2g daily – toxic.
Older patients & those with renal impairment should receive starting doses of only 500mg/day.
MTX
A/E –
Hepatotoxicity –
Seen with long-term Rx – as in psoriasis & RA. Cumulative doses at or above 4.0 kg have been considered risky for Htoxicity.
2) Hematological effects – Pancytopenia presents with greatest potential for loss of life d/t Mtx, common with rheumat Rx, far fewer reports in dermat pts.
3) Carcinogenesis – incidences lymphomas, esp with use of Mtx in collagen vascular ds.
4) GI – N,V,D & ulcerative stomatitis. Presence of severe D with US requires cessation of Mtx Rx.
5) Reproductive effects –
Mtx has long been considered a potent teratogen & abortifacient. Women of child bearing age who take mtx should use reliable birth control.
6) Renal – high dose Rx (50-250mg/m2) renal toxicity secondary to pptn of mtx in renal tubules.
7) Pul toxicity – rarely, acute pneumonitis. Can occur with extremely small doses, life threatening if mtx is not stopped.
5-FU
A/E –
M/c ones localized to areas of Rx & include erythema, irritation, burning pain, pruritis, hypo-/hyperpigmentation. Also allergic contact dermatitis has been reported.
Sys a/e are extremely rare with top appln. However there is a single case report of life threatening toxicity in a patient treated with top 5% FU (who was found to have defcy of the key enz in metabolism of 5-FU, DPD)
Az
A/E –
Immunosuppression - The major side effect of azathioprine is bone marrow suppression, including leukopenia (common), thrombocytopenia (less common), and/or anemia (uncommon)
2) carcinogenesis- (related to immunosuppression)
The m/c malignancies a/w A in dermatological set up are – lymphoproliferative & SCCs.
3) Infections – d/t immunosuppression
Typically seen with high doses, or those on multiple immunosuppressive agents (eg organ transplant pts)
Eg. Herpes v, HPV, scabies etc.
4) HS synd
5) GI – NVD, rarely pancreatitis.
6) Hepatic – chronic admn of A has been a/w uncommon but life threatening hepatic damage. LFT monitoring mandatory
7) Teratogenicity
MMF
A/E –
The principal toxicities of MMF are gastrointestinal and hematologic. These include leukopenia, pure red cell aplasia, diarrhea, and vomiting. There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus; progressive multifocal leukoencephalopathy also has been reported in conjunction with the administration of MMF.
HU
A/E –
Myelosuppression-
m/c
Mild megaloblastic changes, frank anemia, leukopenia
2) Cut a/e-
Dermatomyositis-like eruption, lichenoid drug eruption resembling chronic GVHD, leg ulcers, limited & reversible alopecia.
C/I-
A: P (D), DA
R: cardiopul, hemat, hep, renal, inf