1st Drug List Your guide to 1500+ drugs online!     Bookmark 1stDrugList.com

Search for anything:

Rapamune Side Effects, and Drug Interactions - Sirolimus

Rapamune Side Effects, and Drug Interactions - Sirolimus

SIDE EFFECTS

Rapamune® Oral Solution:   The incidence of adverse reactions was determined in two randomized, double-blind, multicenter controlled trials in which 499 renal transplant patients received Rapamune Oral Solution 2 mg/day, 477 received Rapamune Oral Solution 5 mg/day, 160 received azathioprine, and 124 received placebo. All patients were treated with cyclosporine and corticosteroids. Data ( ≥ 12 months post-transplant) presented in the table below show the adverse reactions that occurred in any treatment group with an incidence of ≥ 20%.

Specific adverse reactions associated with the administration of Rapamune Oral Solution occurred at a significantly higher frequency than in the respective control group. For both Rapamune Oral Solution 2 mg/day and 5 mg/day these include hypercholesterolemia, hyperlipemia, hypertension, and rash; for Rapamune Oral Solution 2 mg/day acne; and for Rapamune Oral Solution 5 mg/day anemia, arthralgia, diarrhea, hypokalemia, and thrombocytopenia. The elevations of triglycerides and cholesterol and decreases in platelets and hemoglobin occurred in a dose-related manner in patients receiving Rapamune.

Patients maintained on Rapamune Oral Solution 5 mg/day, when compared to patients on Rapamune Oral Solution 2 mg/day, demonstrated an increased incidence of the following adverse events: anemia, leukopenia, thrombocytopenia, hypokalemia, hyperlipemia, fever, and diarrhea.

 

ADVERSE EVENTS OCCURRING AT A FREQUENCY OF ≥ 20% IN ANY TREATMENT GROUP IN PREVENTION OF ACUTE RENAL REJECTION TRIALS (%) a AT ≥ 12 MONTHS POST-TRANSPLANTATION FOR STUDIES 1 AND 2 Body System Rapamune® Oral Solution 2 mg/day Rapamune® Oral Solution 5 mg/day Azathioprine 2-3 mg/kg/day Placebo Adverse Event Study 1 (n = 281) Study 2 (n = 218) Study 1 (n = 269) Study 2 (n = 208) Study 1 (n = 160) Study 2 (n = 124) Body As A Whole Abdominal pain 28 29 30 36 29 30 Asthenia 38 22 40 28 37 28 Back pain 16 23 26 22 23 20 Chest pain 16 18 19 24 16 19 Fever 27 23 33 34 33 35 Headache 23 34 27 34 21 31 Pain 24 33 29 29 30 25 Cardiovascular System Hypertension 43 45 39 49 29 48 Digestive System Constipation 28 36 34 38 37 31 Diarrhea 32 25 42 35 28 27 Dyspepsia 17 23 23 25 24 34 Nausea 31 25 36 31 39 29 Vomiting 21 19 25 25 31 21 Hemic And Lymphatic System Anemia 27 23 37 33 29 21 Leukopenia 9 9 15 13 20 8 Thrombocytopenia 13 14 20 30 9 9 Metabolic And Nutritional Creatinine increased 35 39 37 40 28 38 Edema 24 20 16 18 23 15 Hypercholesteremia 38 43 42 46 33 23  (See WARNINGSand    PRECAUTIONS ) Hyperkalemia 15 17 12 14 24 27 Hyperlipemia 38 45 44 57 28 23  (See WARNINGSand    PRECAUTIONS ) Hypokalemia 17 11 21 17 11 9 Hypophosphatemia 20 15 23 19 20 19 Peripheral edema 60 54 64 58 58 48 Weight gain 21 11 15 8 19 15 Musculoskeletal System Arthralgia 25 25 27 31 21 18 Nervous System Insomnia 14 13 22 14 18 8 Tremor 31 21 30 22 28 19 Respiratory System Dyspnea 22 24 28 30 23 30 Pharyngitis 17 16 16 21 17 22 Upper respiratory infection 20 26 24 23 13 23 Skin And Appendages Acne 31 22 20 22 17 19 Rash 12 10 13 20 6 6 Urogenital System Urinary tract infection 20 26 23 33 31 26 a: Patients received cyclosporine and corticosteroids.

At 12 months, there were no significant differences in incidence rates for clinically important opportunistic or common transplant-related infections across treatment groups, with the exception of mucosal infections with Herpes simplex , which occurred at a significantly greater rate in patients treated with Rapamune 5 mg/day than in both of the comparator groups.

The table below summarizes the incidence of malignancies in the two controlled trials for the prevention of acute rejection. At 12 months following transplantation, there was a very low incidence of malignancies and there were no significant differences among treatment groups.

 

INCIDENCE (%) OF MALIGNANCIES IN PREVENTION OF ACUTE RENAL REJECTION TRIALS: AT 12 MONTHS POST-TRANSPLANT a   Rapamune® Oral Solution 2 mg/day Rapamune® Oral Solution 5 mg/day Azathioprine 2-3 mg/kg/day Placebo Malignancy (n = 511) (n = 493) (n = 161) (n = 130) Lymphoma/lymphoproliferative disease 0.4 1.4 0.6 0 Non-melanoma skin carcinoma 0.4 1.4 1.2 3.1 Other malignancy 0.6 0.6 0 0 a: Patients received cyclosporine and corticosteroids.

Among the adverse events that were reported at a rate of ≥3% and <20%, the following were more prominent in patients maintained on Rapamune 5 mg/day, when compared to patients on Rapamune 2 mg/day: epistaxis, lymphocele, insomnia, thrombotic thrombocytopenic purpura (hemolytic-uremic syndrome), skin ulcer, increased LDH, hypotension, facial edema.

The following adverse events were reported with ≥3% and <20% incidence in patients in any Rapamune treatment group in the two controlled clinical trials for the prevention of acute rejection, BODY AS A WHOLE: abdomen enlarged, abscess, ascites, cellulitis, chills, face edema, flu syndrome, generalized edema, hernia, Herpes zoster infection, lymphocele, malaise, pelvic pain, peritonitis, sepsis; CARDIOVASCULAR SYSTEM: atrial fibrillation, congestive heart failure, hemorrhage, hypervolemia, hypotension, palpitation, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombophlebitis, thrombosis, vasodilatation; DIGESTIVE SYSTEM: anorexia, dysphagia, eructation, esophagitis, flatulence, gastritis, gastroenteritis, gingivitis, gum hyperplasia, ileus, liver function tests abnormal, mouth ulceration, oral moniliasis, stomatitis; ENDOCRINE SYSTEM: Cushing's syndrome, diabetes mellitus, glycosuria; HEMIC AND LYMPHATIC SYSTEM: ecchymosis, leukocytosis, lymphadenopathy, polycythemia, thrombotic thrombocytopenic purpura (hemolytic-uremic syndrome); METABOLIC AND NUTRITIONAL: acidosis, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, dehydration, healing abnormal, hypercalcemia, hyperglycemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased, weight loss; MUSCULOSKELETAL SYSTEM: arthrosis, bone necrosis, leg cramps, myalgia, osteoporosis, tetany: NERVOUS SYSTEM: anxiety, confusion, depression, dizziness, emotional lability, hypertonia, hypesthesia, hypotonia, insomnia, neuropathy, paresthesia, somnolence; RESPIRATORY SYSTEM: asthma, atelectasis, bronchitis, cough increased, epistaxis, hypoxia, lung edema, pleural effusion, pneumonia, rhinitis, sinusitis; SKIN AND APPENDAGES: fungal dermatitis, hirsutism, pruritus, skin hypertrophy, skin ulcer, sweating; SPECIAL SENSES: abnormal vision, cataract, conjunctivitis, deafness, ear pain, otitis media, tinnitus; UROGENITAL SYSTEM: albuminuria, bladder pain, dysuria, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, nocturia, oliguria, pyelonephritis, pyuria, scrotal edema, testis disorder, toxic nephropathy, urinary frequency, urinary incontinence, urinary retention.

Less frequently occurring adverse events included: mycobacterial infections, Epstein-Barr virus infections, and pancreatitis.

Rapamune® Tablets:   The safety profile of the tablet did not differ from that of the oral solution formulation. The incidence of adverse reactions up to 12 months was determined in a randomized, multicenter controlled trial (Study 3) in which 229 renal transplant patients received Rapamune Oral Solution 2 mg once daily and 228 patients received Rapamune Tablets 2 mg once daily. All patients were treated with cyclosporine and corticosteroids. The adverse reactions that occurred in either treatment group with an incidence of ≥20% in Study 3 are similar to those reported for Studies 1 & 2. There was no notable difference in the incidence of these adverse events between treatment groups (oral solution versus tablets) in Study 3, with the exception of acne, which occurred more frequently in the oral solution group, and tremor which occurred more frequently in the tablet group, particularly in Black patients.

The adverse events that occurred in patients with an incidence of ≥3% and <20% in either treatment group in Study 3 were similar to those reported in Studies 1 & 2. There was no notable difference in the incidence of these adverse events between treatment groups (oral solution versus tablets) in Study 3, with the exception of hypertonia, which occurred more frequently in the oral solution group and diabetes mellitus which occurred more frequently in the tablet group. Hispanic patients in the tablet group experienced hyperglycemia more frequently than Hispanic patients in the oral solution group. In Study 3 alone, menorrhagia, metrorrhagia, and polyuria occurred with an incidence of ≥3% and <20%.

The clinically important opportunistic or common transplant-related infections were identical in all three studies and the incidences of these infections were similar in Study 3 compared with Studies 1 & 2. The incidence rates of these infections were not significantly different between the oral solution and tablet treatment groups in Study 3.

In Study 3 (at 12 months), there were two cases of lymphoma/lymphoproliferative disorder in the oral solution treatment group (0.8%) and two reported cases of lymphoma/lymphoproliferative disorder in the tablet treatment group (0.8%). These differences were not statistically significant and were similar to the incidences observed in Studies 1 & 2.

Other clinical experience:   Cases of pneumonitis with no identified infectious etiology, sometimes with an interstitial pattern, have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the pneumonitis has resolved upon discontinuation of Rapamune. There have been rare reports of pancytopenia.

 

DRUG INTERACTIONS

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-glycoprotein. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

Cyclosporine capsules MODIFIED:

Rapamune Oral Solution:   In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean C _max and AUC of sirolimus were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C _max and AUC were increased by 37% and 80%, respectively, compared to administration of sirolimus alone.

Mean cyclosporine C _max and AUC were not significantly affected when sirolimus was given simultaneously or when administered 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration.

Rapamune Tablets:   In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus (Rapamune Tablets) either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean C _max and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus C _max and AUC were both increased by only 33% compared with administration of sirolimus alone.

Because of the effect of cyclosporine capsules (MODIFIED), it is recommended that sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED), (see DOSAGE AND ADMINISTRATION ).

Cyclosporine oral solution:   In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m ² /day was administered simultaneously with Sandimmune® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (%CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune® Oral Solution (cyclosporine oral solution) administration. However, the %CV was higher (range 85.9%-165%) than those from previous studies.

Sandimmune® Oral Solution (cyclosporine oral solution) is not bioequivalent to Neoral® Oral Solution (cyclosporine oral solution MODIFIED), and should not be used interchangeably. Although there is no published data comparing Sandimmune® Oral Solution (cyclosporine oral solution) to SangCya® Oral Solution (cyclosporine oral solution [MODIFIED]), they should not be used interchangeably. Likewise, Sandimmune® Soft Gelatin Capsules (cyclosporine capsules) are not bioequivalent to Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) and should not be used interchangeably.

Diltiazem:   The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus C _max , t _max , and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus should be monitored and a dose adjustment may be necessary.

Ketoconazole:   Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of Rapamune Oral Solution, as reflected by increases in sirolimus C _max , t _max , and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t _1/2 of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. It is recommended that sirolimus oral solution and oral tablets should not be administered with ketoconazole.

Rifampin:   Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20 mg-dose of sirolimus, greatly increased sirolimus oral-dose clearance by 5.5-fold (range = 2.8 to 10), which represents mean decreases in AUC and C _max of about 82% and 71%, respectively. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered.

Drugs which may be coadministered without dose adjustment

Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. A synopsis of the type of study performed for each drug is provided. Sirolimus and these drugs may be coadministered without dose adjustments.

Acyclovir:   Acyclovir, 200 mg, was administered once daily for 3 days followed by a single 10-mg dose of sirolimus oral solution on day 3 in 20 adult healthy volunteers.

Digoxin:   Digoxin, 0.25 mg, was administered daily for 8 days and a single 10-mg dose of sirolimus oral solution was given on day 8 to 24 healthy volunteers.

Glyburide:   A single 5-mg dose of glyburide and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Sirolimus did not affect the hypoglycemic action of glyburide.

Nifedipine:   A single 60-mg dose of nifedipine and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers.

Norgestrel/ethinyl estradiol (Lo/Ovral®):   Sirolimus oral solution, 2 mg, was given daily for 7 days to 21 healthy female volunteers on norgestrel/ethinyl estradiol.

Prednisolone:   Pharmacokinetic information was obtained from 42 stable renal transplant patients receiving daily doses of prednisone (5-20 mg/day) and either single or multiple doses of sirolimus oral solution (0.5-5 mg/m ² q 12h).

Sulfamethoxazole/trimethoprim (Bactrim®):   A single oral dose of sulfamethoxazole (40 mg)/trimethoprim, (80 mg) was given to 15 renal transplant patients receiving daily oral doses of sirolimus (8 to 25 mg/m ² ).

top

Popular Searches:
weight loss	ultram	penis enlargement	hydrocodone	antibiotic