Drug interactions -summary

+ Temsirolimus

Azole antifungal eg fluconazole,itraconazole, ketoconazole, posconazole, voriconazole-

plasma concentration of temsirolimus concentrations elevated. Monitor temsirolimus
concentration and observe patient toxicity when starting or stopping an azole antifungal agent. Adjust temsirolimus doses as needed

Cylcosporine-

plasma concentration and active metabolite of Temisirolimus elevated resulting in increased toxicity

CYP-4503A4/5 inducers eg. dexamethasone, ribabutin,rifampin, phenytoin -

avoid concomittant use of strong CYP3A4 inducers. If use cannot be avoided,
consider increasing the tersirolimus dose to 50mg weekly.

CYP-4503A inhibitors eg. atazanavir, clarithromycin, diltiazem -

temsirolumus plasma levels elevated increasing risk  of adverse reactions.
Closely monitor temsirlomus  when starting, stopping or changing dose. Adjust
dose of temsirolimus as needed.

Diltiazem

plasma sirolumus the active metabolite of temsirolimus may be elevated,
increasing risk of toxicity

Myocophenolate

mycophenolate acid trough plasma concentration elevated by sirolumus
increasing risk of adverse reactions

St Johns wart

St Johns wart may decrease tersirolimus plasma concentration .
Avoid concomittant administration

Sunitinab

combination of temsirolimus and sunitinib resulted in dose limiting toxicites
requiring hospitalisation

Temsirolimus + tacrolimus

tacrolimus trough plasma  concentrations reduced by sirolimus , decreasing
pharmacologic effect. Monitor tacrolimus trough levels after starting temsirolimus
and adjust dose as needed 
 

Advanced renal cell carcinoma

Most common adverse reactions-
anorexia, asthenia, edema, mucositis, nausea, rash

CNS -   dysgeusia  18%      heaache  13%   insomnia  10%

Dermatologic -  acne  9%  dry skin 10%  nail disorder   12%   pruritus  18%
                           rash 45%

GI -                   abdominal pain 20%     anorexia   30%   constipation  18%
                         diarrhea    25%     mucosistis    40%    nausea   35%
                         vomiting   18%

Musculoskeletal -    arthalgia   18%    back pain  18%    myalgia   7%

Respiratory -        cough   24%    dyspnea    25%    epistaxis    10%
                               pharyngitis   10%    rhinitis   9%

Miscellaneous -   asthenia  50%    chest pain  15%     chills  6%  edema  33%
                              infections   18%   pain   25%    pyrexia    22%
                              urinary tract infection 13%      weight loss  17%  

Laboratory abnomalites-

Hematology -   hemoglobib increased  93%  leuckocytes  decreased 30% 
                          lymphocytes decreased   50%  neutrophil dercreased  17%
                          platelets decreased   38%

Chemistry-        akaline phosphatase increased    65%
                           AST increased  35%    glucose increased   85%
                           phosphorus decreased   46% potassium decreased  20%
                           total bilirubin  increased 7% 
                           total  cholesterol increased  85%
                           triglycerides increased   80%                          
 

Special precautions/Warnings-

Hyperglycemia / glucose intolerance- advice patients to report excessive thirst or any
increase in the volume or frequency of urination

Infections - use of temsirolimus may result in immunosuppression. Carefuly observe
patients for occurenence of infections,

Interstitial lung disease - advice patient to promptly report any new or  worsening
respiratory symptoms

Hyperlipemia - test serun cholesetrol and triglycerides before and during treatment
with temsirolimus

Bowel perforation- advice patients to promptly report any new or or worsening
abdominal pain or blood in stools

Renal failure-  cases of rapidly progressive and sometimes fatal renal failure
not clearly related to disease progression occurred in patients who received
temsirolimus

Wound healing-  excercise caution in the use of temsirolimus in perioperative
period

Vaccinations-  avoid the use of live vaccine and close contact with those who have
received live vaccines during treatment period with temsirolimus

Hypersentivity reactions-  use temsirolimus in patients with konwn hypersensitivity
to  an antihistamine or patients who cannot receive an antihistamine for other
medical reasons

Pregnancy-  advice women of child bearing potential to avoid becoming pregnant
throughout treatment  and for 3 months after termsirolimus therapy has stopped

Lactation - decide whether to discontinue the drug or breast feeding depending
upon the importance of the drug to the mother.

Children -safety and efficacy in children have not been established

Monitoring-  laboratory monitoring of patients receiving the drug may need to be
performed more or less frequently at the discretion of the doctor.
Check blood cell counts weekly, and chemistry panels every 2 weeks.
Test serum serum glucose before and after treatment. Test serum cholesterol 
and triglycerides before and after receiving treatment

Indication-

Advanced renal cell carcinoma

Dosage-
Recommended dose is 25mg infused over 30 to 60 minute period once a week.
The treatment should continue until disease progression or unaccepable toxicity occurs.

Premedication- patients should receive prophylactic diphenhydramine 25 to 50mg intravenously IV or similar antihistamine aproximately 30  minutes before the start of each temiirolimus

Storage - Store at 2 to 8C ( 36 to 46F (

1. Inform patients of the possibility of serious adverse reactions, including anaphylaxis,
despite medication with anihistamines and to immediately report any facial swelling or
difficult breathing.

2. Patients are likely to experience increased glucose levels while taking temsirolimus.
This may result an increase dose of insulin and/or hypoglycemic agents. Patients to report
any excessive thirst or frequency of urination to their doctor.

3. Inform patients that may be susceptible to infections while being treated with temsirolimus

4. Warn patients of the possibility of developing interstitial disease, chronic inflammation of
lungs that may rarely result in death.

5. inform patients that should report any new or worsening respiratory symptoms to their
health care provider.

6.Patients may develop  elevated triglycerides and/or cholesterol during treatment. This
may require initiation of an increased dose of an lipid-lowering agent.

7.Warn patients of the possibility of bowel perferoation. Patients should report any new or
woserning of abdominal pain or blood in their stools.

8. Inform patients of the renal failure.

9. Inform patients of a possibility of abnormal wound healing if they have surgery within
a few weeks of initiatiing therapy or during therapy

10. Advice patients with CNS tumors and/or receiving anticoagulants of the increased
risk of developing intracerebral bleeding including fatal outcome while on treatment.

11. Direct patients to inform their doctor if they are taking any of the following-
 anti-epilieptic medicines including carbamazrpine, phenytoin, barbiturates,
St.Johns Wart, rifampin, rifabutin, nefazodone, selective serotonin reuptake inhibitors,   
used to treat depression, antibiotics, or antifungal medicines used to treat infections.

12.Advice patients that vaccination will be less effective while being treated with
temsirolimus. Patients should be told to  avoid the use of live vaccines and come into
close contact with those who have received the vaccines live vaccines while on
temsirolumus

13, Temsirolimus can cause fetal harm. Advice women of child bearing potential  to
avoid becoming pregnant throughout the treatment and for 3 months after temsirolimus
therapy is stopped. Men with partners of child bearing potential should use reliable
contraceptive throughout treatment and are recommended to continue this for 3 months
after the last dose of temsirolimus

Pregnancy- 
Advice women of child bearing potential to avoid becoming pregnant
throughout treatment  and for 3 months after termsirolimus therapy has stopped

Lactation -
Decide whether to discontinue the drug or breast feeding depending
upon the importance of the drug to the mother.

Children -
Safety and efficacy in children have not been established