Drug Interactions - Summary-

+ Everolimus

Azole antifungal eg fluconazole, ketoconazole, voriconazole
Calcium  Channel blockers eg diltiazem, verapramil
CYP3A4 or Pgp inhibitors eg. aprepitant, delavirdine, nefazodone
Macrolide antibiotics eg clarithromycin,erythromycin, telithromycin
Protease inhibitors  eg atazanavir, fosamprenavir, indinavir, nelfinavir,
ritonavir, saquinavir

significant increases in everolimus exposure when everolimus was coadminstered with
  CYP3A4 inhibitor or apg inhibitor. Avoid coadministratun.

CYP3A4/ Pgp inducers eg  carbamazepine, dexamethasone, phenobarbital, phenytoin,
rifampin

coadmin  of everolimus with rifampin decreased everolimus AUC and Cmax.
Avoid coadministration . Consider dose increase of everolimus when administered
with strong inducers of CYP3A4 or pgp , if alterative treatment not possible  

LIST OF DRUGS DURING 2004

Most common adverse reactions-
abdominal pain, asthenia, dehydration, dyspnea, fatigue, infections, pneumonitis, and
stomatitis.

Deaths - caused by acute respiratory failure

CNS -   asthenia   31%    fatigue  30%    headache   18%

Dermatological -  dry skin    11%    pruritus 12%     rash  27%

GI -                anorexia    23%     diarrhea    28%    dyspeusia    8%    nausea    23%
                      stomatitis   42%      vomiting    18%

Respiratory -    cough    28%     dyspnea    22%    epistaxis    15%     pneumonitis  12%

Miscellaneous -   edema   peripheral  23%      infections  and infestation 34%
                               mucosal inflammation  16%  pain in extremity   8%
                               pyrexia   18%

Lab test abnormalites-

Hematology -   hemoglobin decreased  90%   lymphocytes decreased   50%
                          neutrophil decreaed 12%  platelet decreased    21%

Chemistry -          ALT increased   20%    AST increased    23%   
                              Bilirubin increased   2%    cholesterol decreased  74%
                              creatinine increased  48%    glucose decreased   53%
                              phosphate decreased   34%   triglyceride increased   70%

Hypesensitivity  to active substance

Special Precautions/Warnings-

Non infectious pneumonitis -  if reactions are severe discontinue  everolimus therapy,
Use of corticosteroids may be indicated until sypmtoms resolve. Therapy may be reinstituted at a reduced dosage of 5mg daily.

Infections-  localised and systemic including pneumonia, other bacterial infections have
occurred.  Discontinue everolimus therapy and treat with appropiate therapy

Oral ulcerations- mouth ulcers and oral mucositis have occurred. In such cases topical
traments are recommended, but avoid alcohol or peroxide containing mouth washes

Vaccinations-  avoid use of live vaccines and close contact with those who have received
live vaccines

Hypersensitivity - hypersensitivity reactions manifested by  symptoms including  anaphylaxis,dyspnea, flushing, chest pain, angioedema eg  swelling of airways  have been observed

Hepatic function impairment - everolimus has not been studied in patients with severe
hepatic impairment

Pregnancy - advice women of child bearing potential to use an effective method of
contraception while using everolimus for upto 8 weeks after ending treatment
 
Lactation- decide whether to discontinue breast feeding or the drug taking into consideration the importance of the drug to the mother.

Children-  safety and efficacy in children have not been established

Monitoring- elevation of creatinin,usually mild have been reported
Monitor renal function including measurement of urea nitrogen or serum creatinine is
 recommended prior to start of everolimus and periodically thereafter

Indication-

Advanced renal cell carcinoma

Dosage-
Usual dose 10mg once daily at the same time each day

Dosage adjustment - management of severe and/or intolerable adverse reactions may require temporary dose reduction and/or  interruption of everolimus therapy
If dose reduction is required the suggested dose is 5mg daily

Storage - store at 25C ( 77F ). store in original container protect from heat and moisture.

1. Warn patients of development of noninfectious pneumonitis. Advice patients to report
promptly any new or worsening respiratory infection.

2. inform patients of the possibility of developing mouth ulcers, stomatitis, and oral mucositis In such cases mouth washes and/or topiccal treatment are recommended, but these should not contain alcohol.

3. Inform patientsof the need to monitor blood chemistry and hemotology prior to the
start of everolimus therapy and periodically  thereafter.

4. Avoid comcurrent treatment of strong CYP3A and pgp inhibitors and strong CYP3A4 Pgp
inducers. Consider a dose reduction and carfully monitor the patient for clinical response.
Inform your Doctor of all concomittant medications including non-prescription medications
and dietary supplements, you are taking.

5. Advice patients that everolimus is not recommened in patients witrh severe hepatic
impairment. Prescribe  a reduced dosage off everolimus 5mg/day with moderate
hepatic impairment

6. Advice women of child bearing potential that everolimus may cause fetal harm and to
use an effective contraceptive during therapy and for 8 weeks after ending treatment.

Pregnancy -
Advice women of child bearing potential to use an effective method of
contraception while using everolimus for upto 8 weeks after ending treatment
 
Lactation-                                                                                                                            Decide whether to discontinue breast feeding or the drug taking into consideration
the importance of the drug to the mother.

Children- 
Safety and efficacy in children have not been established