Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) Everolimus
2) Everolimus
3) Everolimusum
4) CAS 159351-69-6

1) ASM 981
2) Elidel
3) SDZ ASM 981

1) Rapamycin
2) AY-22989
3) AY-022989
4) Wy-090217
5) Molecular Formula: C51-H79-N-O13
6) CAS 53123-88-9

1) FK-506
2) FR-900506
3) Molecular Formula: C44-H69-NO12-H20
4) CAS 104987-11-3 (anhydrous tacrolimus)
5) CAS 109581-93-3 (tacrolimus monohydrate)

1) CC1-779
2) Temsirolimusum
3) Molecular Formula: C55-H87-NO-16
4) CAS 162635-04-3

Available Forms Sources

A)

1) TACROLIMUS

a) ORAL - Tacrolimus is available for oral administration as capsules containing the equivalent of 1 or 5 milligrams of anhydrous tacrolimus.
b) INTRAVENOUS INFUSION - Tacrolimus is available as a sterile solution containing the equivalent of 5 milligrams of anhydrous tacrolimus in 1 mL for intravenous infusion. Each milliliter also contains 200 mg polyoxyl 60 hydrogenated castor oil (HCO-60) and 80% v/v dehydrated alcohol, USP. Tacrolimus for injection MUST be diluted with normal saline or D5W before use.

2) EVEROLIMUS

a) ORAL - Everolimus is available in 5 mg and 10 mg tablets (Prod Info AFINITOR(R) oral tablets, 2009)

3) SIROLIMUS

a) ORAL - Sirolimus is available as a 1 milligram/milliliter oral solution (Prod Info RAPAMUNE(R) oral solution, oral tablets, 2007).

4) TEMSIROLIMUS

a) INTRAVENOUS - Temsirolimus is available in a of 25 mg/mL vial with a separate diluent and the vials are supplied as a kit in a single carton (Prod Info TORISEL(TM) KIT IV injection, 2007).

B)

1) TACROLIMUS - Tacrolimus is used to prevent or reverse rejection in patients receiving organ transplants and has been tried in a few patients with refractory auto-immune or immune-mediated disorders.
2) EVEROLIMUS - Is a kinase inhibitor used in the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.
3) SIROLIMUS - Sirolimus (also known as rapamycin) is indicated as part of a combination regimen with cyclosporine and corticosteroids for the prophylaxis of organ rejection in patients receiving renal transplants.
4) PIMECROLIMUS - At the time of this review, pimecrolimus is an investigational agent that appears to be effective in the treatment atopic dermatitis in adults and children, allergic and chronic irritant contact dermatitis in adults, and in plaque psoriasis.
5) TEMSIROLIMUS - Temsirolimus is an ester analogue of sirolimus used for the treatment of advanced renal cell carcinoma. It is an inhibitor of mammalian target of rapamycin (mTOR). It binds to an intracellular protein that inhibits the activity of mTOR that controls cell division.

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Tacrolimus, a calcineurin-inhibitor immunosuppressant, is used prophylactically to prevent organ rejection in patients receiving allogenic liver, kidney or heart transplants. It is also used concomitantly with adrenal corticosteroids; in kidney and heart transplant, and used in conjunction with azathioprine or mycophenolate mofetil. It was previously known as FK506.
B) PHARMACOLOGY: Tacrolimus inhibits T-lymphocyte activation, however, the exact mechanism is unknown. It has been suggested that tacrolimus binds to an intracellular protein, FKBP-12. This complex along with calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This effect can prevent the dephosphorylation and translocation of nuclear factor of activated T-cells which results in the inhibition of T-lymphocyte activation (ie, immunosuppression).
C) EPIDEMIOLOGY: Limited information. Overdose has been infrequently reported.
D) WITH THERAPEUTIC USE

1) ADVERSE EVENTS: TACROLIMUS: COMMON: Adverse events occurring in up to 40% of patients following kidney, liver or heart transplant include: tremor, hypertension, abnormal renal function, constipation, diarrhea, abdominal pain, nausea, headache, insomnia, fever, asthenia, paraesthesia, anemia, leukopenia, peripheral edema, asthenia, pain, hypophosphatemia, hypomagnesemia, hyperlipidemia, hyperkalemia, hyperglycemia, diabetes mellitus, infection, CMV infection, urinary tract infection, bronchitis, and pericardial effusion.
2) OTHER: CNS effects are the most common events reported. The most severe events include posterior reversible encephalopathy syndrome (PRES), delirium and coma. Symptoms that may develop with PRES can include headache, altered mental status, seizures, visual disturbances, and hypertension. Usually these events will resolve with symptomatic care (ie, antihypertensives) and discontinuation of therapy. Coma and delirium, in the absence of PRES, appear to be dose dependent. NEPHROTOXICITY (acute or chronic) can develop in high doses. It is usually characterized by an increase in serum creatinine, changes to the kidney graft life and histologic changes on renal biopsy. Events are typically progressive. HEMATOLOGIC effects have included anemia, leukocytosis and thrombocytopenia. LYMPHOMA and other malignancies can develop as a result of immunosuppressive therapy. INFECTION: Patients are at increased risk of developing bacterial, viral, fungal, and protozoal infections with therapy. INFREQUENT: Hemolytic uremic syndrome, pneumonitis. IMMUNOLOGIC: Anaphylaxis has been reported with the intravenous formulations; frequency not known.
3) SIROLIMUS and TEMSIROLIMUS: These agents have similar adverse events to tacrolimus.

E) WITH POISONING/EXPOSURE

1) OVERDOSE: TACROLIMUS: Acute overdoses of up to 30 times the therapeutic dose have occurred and almost all cases have been asymptomatic and recovered without sequelae. In patients who have received inadvertent overdoses of tacrolimus, the effects have been similar to those reported at therapeutic dose. SIROLIMUS: Limited data; events are anticipated to be similar to adverse events reported with tacrolimus. TEMSIROLIMUS: Doses greater than 25 mg may result in serious events including: thrombosis, bowel perforation, interstitial lung disease, seizures and psychosis.

0.2.3)

A) WITH THERAPEUTIC USE

1) Increased blood pressure has been reported with therapy (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

0.2.20)

A) TEMSIROLIMUS is classified as FDA pregnancy category D. EVEROLIMUS is classified as FDA pregnancy category C by the manufacturer of Zortress(R). SIROLIMUS and TACROLIMUS are classified as FDA pregnancy category C. Controlled studies in pregnant women are lacking. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. An increased incidence of malformations and developmental variations has been observed in rabbits given tacrolimus at doses greater than the maximum human daily dose. In rats and rabbits exposed to everolimus, embryofetal toxicities were observed. Tacrolimus is excreted in human milk. Everolimus is excreted in rat milk. In male rats, fertility was affected by exposure to everolimus.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Monitor vital signs and neurologic status. Monitor fluid status and electrolytes following significant vomiting and/or diarrhea. Administer oral or IV fluids and replace electrolytes as needed. Antidiarrheals may be indicated following persistent symptoms. Seizure activity may develop; treat with IV benzodiazepines, barbiturates. Mild hypertension usually does not require treatment.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Nitroprusside or nitroglycerin may be considered for significant or persistent hypertension. Monitor CBC with differential and monitor for signs of serious infection (eg, bacterial, viral, fungal, protozoal). Begin anti-infective treatment as soon as possible. Patients may also be at risk to develop anemia and thrombocytopenia. Transfuse packed red blood cells and platelets as indicated. Obtain a baseline ECG in patients (ie, preexisting congestive heart failure, bradyarrhythmias, antiarrhythmic medications) at risk to develop QT prolongation or as indicated.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not indicated because CNS effects can develop and may include seizures.
2) HOSPITAL: Activated charcoal may be considered following a recent ingestion, if the patient is not vomiting and the airway is supported.

D) AIRWAY MANAGEMENT

1) Airway management is unlikely to be necessary following a mild to moderate exposure. Ensure adequate ventilation and intubation as necessary in patients that develop seizure activity or significant CNS depression.

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) Based on high protein binding of these agents, hemodialysis is not anticipated to be effective following overdose.

G) PATIENT DISPOSITION

1) HOME CRITERIA: An asymptomatic adult with an inadvertent ingestion of 1 extra dose can be monitored at home. An asymptomatic child that ingests 1 dose can be monitored at home if reliable adult supervision is present. If the amount ingested is unknown the child should be observed in a healthcare facility.
2) OBSERVATION CRITERIA: All patients with a deliberate self-harm ingestion or inadvertent ingestion of more than 2 extra doses should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with an unintentional ingestion of more than 1 dose or an unknown amount should be observed in a healthcare facility until any symptoms resolve and adequate follow-up can be provided as needed.
3) ADMISSION CRITERIA: Patients demonstrating severe fluid and electrolyte imbalance should be admitted. Patients with persistent mental status changes and seizures should be admitted to an ICU setting.
4) CONSULT CRITERIA: Consult with a medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

H) PHARMACOKINETICS

1) TACROLIMUS: Absorption after oral administration is incomplete and variable. Tmax: Immediate release: 1.5 to 3 hours; Extended release: 2 to 3 hours. Plasma protein binding is approximately 99%, mainly to albumin. The volume of distribution of tacrolimus in liver transplant patients is approximately 0.85 L/kg. It is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). Excretion: Primarily occurs in the feces; minor excretion in urine. ELIMINATION: IMMEDIATE RELEASE: An orally administered radiolabeled dose of tacrolimus in healthy adults resulted in an elimination half-life of 31.9 +/- 10.5 hours whereas it was 48.4 +/- 12.3 hours based on tacrolimus concentrations. EXTENDED RELEASE: Elimination half-life was 37.9 +/- 3.4 hours following oral administration in healthy volunteers.
2) EVEROLIMUS: It is approximately 74% protein bound. Tmax is 1 to 2 hours in patients with advanced solid tumors following oral administration of everolimus 5 to 70 mg. Metabolism: Substrate of CYP3A4 and p-glycoprotein. Elimination half-life: approximately 30 hours.
3) SIROLIMUS: Rapidly absorbed following oral administration; bioavailability is approximately 14%. It is approximately 92% protein bound, mainly to albumin. Volume of distribution is 12 +/- 7.52 L/kg. It is extensively metabolized in the liver by O-demethylation and/or hydroxylation. Elimination half-life of sirolimus after multiple dosing in stable renal transplant patients was approximately 62 +/- 16 hours.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) ADVERSE EVENTS: TACROLIMUS: COMMON: Adverse events occurring in up to 40% of patients following kidney, liver or heart transplant include: tremor, hypertension, abnormal renal function, constipation, diarrhea, abdominal pain, nausea, headache, insomnia, fever, asthenia, paraesthesia, anemia, leukopenia, peripheral edema, asthenia, pain, hypophosphatemia, hypomagnesemia, hyperlipidemia, hyperkalemia, hyperglycemia, diabetes mellitus, infection, CMV infection, urinary tract infection, bronchitis, and pericardial effusion.
2) OTHER: CNS effects are the most common events reported. The most severe events include posterior reversible encephalopathy syndrome (PRES), delirium and coma. Symptoms that may develop with PRES can include headache, altered mental status, seizures, visual disturbances, and hypertension. Usually these events will resolve with symptomatic care (ie, antihypertensives) and discontinuation of therapy. Coma and delirium, in the absence of PRES, appear to be dose dependent. NEPHROTOXICITY (acute or chronic) can develop in high doses. It is usually characterized by an increase in serum creatinine, changes to the kidney graft life and histologic changes on renal biopsy. Events are typically progressive. HEMATOLOGIC effects have included anemia, leukocytosis and thrombocytopenia. LYMPHOMA and other malignancies can develop as a result of immunosuppressive therapy. INFECTION: Patients are at increased risk of developing bacterial, viral, fungal, and protozoal infections with therapy. INFREQUENT: Hemolytic uremic syndrome, pneumonitis. IMMUNOLOGIC: Anaphylaxis has been reported with the intravenous formulations; frequency not known.
3) SIROLIMUS and TEMSIROLIMUS: These agents have similar adverse events to tacrolimus.

E)

1) OVERDOSE: TACROLIMUS: Acute overdoses of up to 30 times the therapeutic dose have occurred and almost all cases have been asymptomatic and recovered without sequelae. In patients who have received inadvertent overdoses of tacrolimus, the effects have been similar to those reported at therapeutic dose. SIROLIMUS: Limited data; events are anticipated to be similar to adverse events reported with tacrolimus. TEMSIROLIMUS: Doses greater than 25 mg may result in serious events including: thrombosis, bowel perforation, interstitial lung disease, seizures and psychosis.

Vital Signs

3.3.1)

A) WITH THERAPEUTIC USE

1) Increased blood pressure has been reported with therapy (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) BLURRED VISION (3% to 19%) has been reported with tacrolimus, primarily following intravenous administration (Fung et al, 1991; Shapiro et al, 1990).
2) PHOTOPHOBIA (3% to 15%) has been reported with tacrolimus, primarily following intravenous administration (Fung et al, 1991; Shapiro et al, 1990).
3) AMBLYOPIA has been reported in greater than 3% and less than 15% of tacrolimus-treated patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

3.4.4)

A) WITH THERAPEUTIC USE

1) TINNITUS

a) Tinnitus has been reported less frequently with tacrolimus therapy (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015; Fung et al, 1991).
b) CASE REPORT: A 38-year-old woman developed sudden hearing loss with tinnitus approximately 17 days after beginning tacrolimus therapy, 5 mg twice daily initially with an increase to 10 mg twice daily, following a kidney-pancreas transplantation. The patient's serum tacrolimus level peaked at 34.9 ng/mL 11 days later (therapeutic range: 10 to 20 ng/mL). The patient's hearing gradually recovered following a dosage reduction to 6 mg twice daily with a serum tacrolimus level of 9.7 ng/mL (Min et al, 1999).

Cardiovascular

3.5.2)

A) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Mild to moderate hypertension was reported in up to 62% of patients receiving tacrolimus (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

B) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Chest pain, hypotension, tachycardia and abnormal ECG have occurred in greater than 3% and less than 15% of tacrolimus-treated patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

C) CARDIOMYOPATHY

1) WITH THERAPEUTIC USE

a) CASE SERIES

1) Atkison et al (1995) described 5 pediatric patients (age 7 months to 5 years) who developed concentric hypertrophic cardiomyopathy after receiving tacrolimus for liver and/or small bowel transplantation. Cardiomyopathy was detected as a result of routine echocardiographs. Three patients developed serious side effects, such as congestive heart failure. The other 2 patients had minor adverse effects, such as edema. In most patients, cardiomyopathy regressed or resolved upon discontinuing tacrolimus or decreasing the dose.

D) ANGINA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 20-year-old bone marrow transplant recipient experienced severe chest pain and dyspnea 24 days after beginning intravenous tacrolimus therapy. ECG showed ST depression and lab analysis revealed an elevated tacrolimus level of 45.4 ng/mL. Coagulation studies showed the serum thrombomodulin was elevated to 6.0 ng/mL, suggesting endothelial damage, and low antithrombin III activity. The patient gradually recovered with a normalization of her antithrombin III (Uchida et al, 2000).

E) ATRIAL FIBRILLATION

1) WITH THERAPEUTIC USE

a) SIROLIMUS: Transient atrial fibrillation was reported in one patient who inadvertently ingested 150 mg of sirolimus (Prod Info Rapamune(R), sirolimus, 1999).

Respiratory

3.6.2)

A) PLEURAL EFFUSION

1) WITH THERAPEUTIC USE

a) Pleural effusion (up to 30%) has been reported during clinical trials (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

B) ATELECTASIS

1) WITH THERAPEUTIC USE

a) Atelectasis (up to 28%) has been reported during clinical trials (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

C) DYSPNEA

1) WITH THERAPEUTIC USE

a) Dyspnea (up to 29%) has been reported during clinical trials (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

D) RESPIRATORY SYMPTOM

1) WITH THERAPEUTIC USE

a) Asthma, bronchitis, cough, pulmonary edema, pneumonia, rhinitis, sinusitis and voice alterations have been reported in greater than 3% and less than 15% of tacrolimus-treated patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

E) PNEUMONITIS

1) WITH THERAPEUTIC USE

a) SIROLIMUS

1) In a case series of 217 renal transplant patients who received sirolimus at one center over a 7 year period, 24 (11%) patients developed pneumonitis. Presenting symptoms included cough (n=23), fatigue (n=20), fever (n=16) and dyspnea (n=8). Pulmonary infiltrates were found on radiography in all patients. Computed tomography findings included patchy bilateral asymmetrical peripheral consolidation (bronchiolitis obliterans-organizing pneumonia) (n=19), reticular and ground-glass opacities (n=4) and lobar consolidation (n=1). Following sirolimus withdrawal, 19 patients improved within 2 weeks without intervention and 3 patients required corticosteroids for 2 weeks. Chest radiography and CT were normal within 6 months in 22 patients, and all patients have remained free of pneumonitis 1 to 6 years after drug withdrawal (Champion et al, 2006).

F) INTERSTITIAL LUNG DISEASE

1) WITH POISONING/EXPOSURE

a) Doses of greater than 25 mg temsirolimus may increase the risk of developing interstitial lung disease (Prod Info TORISEL(TM) KIT IV injection, 2007).

Neurologic

3.7.2)

A) TREMOR

1) WITH THERAPEUTIC USE

a) Common adverse effects of tacrolimus have involved the central nervous system, and include tremors (up to 56%) and insomnia (32% to 64%) (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

B) COMA

1) WITH THERAPEUTIC USE

a) Coma and delirium have been associated with high tacrolimus plasma concentrations (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

C) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures, agitation, confusion, dizziness and incoordination have been reported in greater than 3% and less than 15% of tacrolimus-treated patients (Prod Info PROGRAF(R) capsules, injection, 2005).

2) WITH POISONING/EXPOSURE

a) Doses of greater than 25 mg temsirolimus may increase the risk of developing seizures (Prod Info TORISEL(TM) KIT IV injection, 2007).

D) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache (44% to 64%) has been reported after oral or IV use (Prod Info PROGRAF(R) capsules, injection, 2005; Fung et al, 1990).

E) PARESTHESIA

1) WITH THERAPEUTIC USE

a) Paresthesias (23% to 40%) has been reported primarily after oral or IV use (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015; Fung et al, 1990).
b) CASE REPORT: A 62-year-old man developed weakness and paresthesias approximately 14 days after beginning tacrolimus as rescue replacement of cyclosporin. Nerve conduction velocities were lower than normal and distal latencies were prolonged, which is consistent chronic inflammatory demyelinating polyneuropathy. The patient improved upon withdrawal of tacrolimus and administration of prednisone as well as 5 courses of plasmapheresis with albumin replacement (Haviv et al, 1999).

F) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) CASE REPORT: Confusion and disorientation, with memory loss and depressive ideas, were reported in a 64-year-old renal transplant recipient who was on tacrolimus therapy and had renal function impairment, evidenced by elevated serum creatinine levels. The patient experienced a seizure and her neurological status continued to deteriorate progressing to a comatose state. A CT scan showed moderate parieto-occipital cerebral atrophy. The patient gradually recovered, including improvement of renal function, following cessation of tacrolimus therapy and administration of prednisone (Grimbert et al, 1999).

G) CEREBRAL HEMORRHAGE

1) WITH THERAPEUTIC USE

a) TEMSIROLIMUS: Patients receiving temsirolimus therapy, with a history of central nervous system tumors and/or receiving anticoagulant therapy, may be at increased risk to develop an intracerebral bleed (Prod Info TORISEL(TM) KIT IV injection, 2007).

H) DRUG INTERACTION

1) WITH THERAPEUTIC USE

a) When given as rescue therapy, the incidence of CNS effects is greater with tacrolimus plus cyclosporine compared with tacrolimus alone (started 24 hours after discontinuance of cyclosporine) (Fung et al, 1991).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting have been reported frequently by patients treated with these agents (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
b) SIROLIMUS: An observational study was conducted to assess the possible clinical outcomes following a sirolimus overdose. Of the 5 cases, 3 occurred accidentally in young children and 2 in adults (an administration error in one case and suicide intent in the other). The 3 children ranged in age from almost 2 to 3 years-old and two remained asymptomatic. A 2.5 year-old boy ingested 3 mg and received a dose of activated charcoal 4 hours after exposure. He developed a mild fever and gastroenteritis and had an increase in alkaline phosphatase that were likely related to the overdose. He recovered completely (Ceschi et al, 2015).

B) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Abdominal pain (33%) and anorexia (up to 34%), have been reported by patients administered tacrolimus (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015). Mucositis (41%) was the most frequently reported gastrointestinal event with temsirolimus therapy; anorexia (32%) and abdominal pain (21%) were also common (Prod Info TORISEL(TM) KIT IV injection, 2007).

C) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea (up to 72%) has been reported by patients administered tacrolimus (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015), and reported in 27% of temsirolimus-treated patients (Prod Info TORISEL(TM) KIT IV injection, 2007).

D) CONSTIPATION

1) WITH THERAPEUTIC USE

a) Constipation (up to 36%) is commonly reported with patients administered tacrolimus (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

E) DRUG INTERACTION

1) WITH THERAPEUTIC USE

a) The incidence of GI effects is greater during combined therapy with cyclosporine (Fung et al, 1990). Cyclosporine should be discontinued at least 24 to 48 hours prior to initiation of tacrolimus (Fung et al, 1990).

F) PERFORATION OF INTESTINE

1) WITH POISONING/EXPOSURE

a) Doses of greater than 25 mg temsirolimus may increase the risk of developing a bowel perforation (Prod Info TORISEL(TM) KIT IV injection, 2007).

Hepatic

3.9.2)

A) ABNORMAL LIVER FUNCTION

1) WITH THERAPEUTIC USE

a) Abnormal liver function tests have been reported following tacrolimus and temsirolimus therapy (Prod Info TORISEL(TM) KIT IV injection, 2007; Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

B) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) Hepatitis, jaundice and liver damage have been reported in greater than 3% and less than 15% of tacrolimus-treated patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

Genitourinary

3.10.2)

A) URINARY TRACT INFECTIOUS DISEASE

1) Urinary tract infections have occurred in up to 34% of patients administered tacrolimus during clinical studies (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

B) RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) TACROLIMUS

1) SUMMARY

a) Calcineurin-inhibitors can cause acute or chronic nephrotoxicity especially when given in high doses. Acute nephrotoxicity is usually due to vasoconstriction of the afferent renal arteriole. Typical findings include an increase in serum creatinine, hyperkalemia and/or a decrease in urine output. Nephrotoxicity is usually reversible (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
b) Nephrotoxicity was reported in up to 52% of kidney transplant patients and in 40% and 36% of liver transplant patients administered tacrolimus in the US and European trials, respectively. It was also reported in 59% of heart transplant patients in European randomized trial (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
c) Oliguria has occurred in up to 18% of patients administered tacrolimus during clinical studies (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

2) CASE REPORTS

a) RENAL FAILURE requiring chronic hemodialysis was needed in 1 of 40 heart transplant recipients while receiving tacrolimus as a primary therapy (Fung et al, 1991a).
b) CASE REPORT: Elevated creatinine was reported in a 29-year-old man, 4 years postcadaveric renal transplant, following an intentional overdose of 90 mg (1.5 mg/kg) of tacrolimus. Creatinine peaked at 48 hours to 3.9 mg/dL (baseline 2.2 mg/dL). At 6 month follow-up his creatinine was 1.9 mg/dL (Mrvos et al, 1997).
c) CASE SERIES: A retrospective chart review of 40 patients, who had received tacrolimus following blood stem cell transplantations, showed that more than half of the patients developed a doubling of their baseline serum creatinine (Woo et al, 1997).

b) SIROLIMUS

1) In a study of 15 patients receiving allogenic hematopoietic stem cell transplantation who were treated for chronic graft-versus-host disease with sirolimus, 5 patients developed renal toxicity as defined by an increase in creatinine levels of greater than or equal to 65% times baseline with a creatinine level of 2.0 mg/dL or greater. Time to toxicity was approximately 30 days (range 4 to 73 days) after the start of therapy. In most cases, and effects resolved with the discontinuation or reduction in sirolimus dose. All patients that developed nephrotoxicity had sirolimus blood levels of greater than or equal to 25 ng/mL (Busca et al, 2005).

c) TEMSIROLIMUS

1) Rapidly progressing and sometimes fatal cases of acute renal failure, not clearly associated with disease progression, have been reported in patients receiving temsirolimus therapy. In some cases, hemodialysis was not useful (Prod Info TORISEL(TM) KIT IV injection, 2007).

2) WITH POISONING/EXPOSURE

a) TACROLIMUS

1) CASE REPORT: A 42-year-old healthy woman developed metabolic acidosis and non-oliguric renal failure after inadvertently receiving an estimated daily dose of 2.1 mg/kg/day of tacrolimus over 4 days. Initial laboratory studies obtained approximately 27 hours after the last dose included a serum creatinine of 4 mg/dL. The patient recovered completely following supportive care. Although the patient had a history of hypertension and was on an ACE inhibitor and had recently be given IV contrast, the authors concluded that the patient's rapid response to therapy was consistent with an acute tacrolimus exposure (O'Connor et al, 2008).

C) BLOOD IN URINE

1) WITH THERAPEUTIC USE

a) Hematuria has been reported infrequently in tacrolimus-treated patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

D) UREMIA

1) WITH THERAPEUTIC USE

a) TACROLIMUS

1) CASE REPORT: Hemolytic uremic syndrome was reported in one patient following 9 to 23 months of tacrolimus therapy (Holman et al, 1993).
2) CASE SERIES: A retrospective chart review of 40 patients, who had been administered tacrolimus following blood stem cell transplantations, showed that one patient developed hemolytic-uremic syndrome (Woo et al, 1997).

b) SIROLIMUS

1) In a study of 15 patients receiving allogenic hematopoietic stem cell transplantation who were treated for chronic graft-versus-host disease with sirolimus, one patient developed hemolytic uremic syndrome (Busca et al, 2005).

E) ABNORMAL RENAL FUNCTION

1) WITH THERAPEUTIC USE

a) Decreased renal blood flow has been documented while the filtration fraction generally remains the same (Fung et al, 1991a).

Acid-Base

3.11.2)

A) METABOLIC ACIDOSIS

1) WITH THERAPEUTIC USE

a) Acidosis has been reported in greater than 3% and less than 15% of tacrolimus-treated patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 42-year-old healthy woman developed metabolic acidosis and non-oliguric renal failure after inadvertently receiving an estimated daily dose of 2.1 mg/kg/day of tacrolimus over 4 days. Initial laboratory studies obtained approximately 27 hours after the last dose included a serum bicarbonate of 12 mmol/L, and an arterial pH of 7.2 and pCO2 35 mmHg. The patient recovered completely following fluid and bicarbonate replacement (O'Connor et al, 2008).

B) ALKALOSIS

1) WITH THERAPEUTIC USE

a) Alkalosis has been reported in greater than 3% and less than 15% of tacrolimus-treated patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

Hematologic

3.13.2)

A) ANEMIA

1) WITH THERAPEUTIC USE

a) INCIDENCE: In clinical trials, anemia occurred in up to 47% of patients administered tacrolimus (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
b) PEDIATRIC: Nineteen of 49 pediatric patients receiving tacrolimus for heart transplantation developed moderate (43%) or severe anemia (16%). Two patients with severe anemia had concurrent parvovirus infections that may account for the anemia. Nine patients were treated with erythropoietin of whom 7 responded (Asante-Korang et al, 1996).

B) ECCHYMOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 3.5-year-old girl with steroid-resistant nephrotic syndrome secondary to immunoglobulin M nephropathy was started on tacrolimus and within one week developed diffuse ecchymotic areas, gingival bleeding as well as vomiting, diarrhea and leg pains. Laboratory results included: bleeding time 12.5 (2.5-10), prothrombin 13.6/13 s, partial thromboplastin time 98/30 s, platelet count 307,000/mm(3), hemoglobin 10 gm/dL and normal clotting factors. Tacrolimus was stopped and fresh frozen plasma was given. Four months after the initial episode, the patient still had recurrent ecchymosis. It was found that the child had an inherited glycoprotein IaIIa deficiency. Based on this finding and a possible interaction between acetylsalicylic acid and tacrolimus, the authors suggested these may have contributed to the prolonged symptoms observed (Akl et al, 2008).

C) LEUKOCYTOSIS

1) WITH THERAPEUTIC USE

a) In clinical trials, patients receiving both tacrolimus and temsirolimus developed leukocytosis (Prod Info TORISEL(TM) KIT IV injection, 2007; Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

D) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) TACROLIMUS

1) INCIDENCE: In clinical trials, up to 24% of patients receiving tacrolimus developed thrombocytopenia (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

b) SIROLIMUS

1) Thrombocytopenia was the most common adverse effect reported in a small study (n=15) of patients receiving allogeneic hematopoietic stem cell transplantation that were given sirolimus following the development of chronic graft-versus-host disease. In 3 patients, thrombocytopenia was associated with the presence of platelet autoantibodies. Platelets normalized in 5 patients with the discontinuation or a dose reduction of sirolimus (Busca et al, 2005).

E) HEMOLYTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute hemolytic anemia leading to death was reported in a 17-year-old after administration of tacrolimus. Upon postmortem examination, lymphoproliferative disorder was discovered (DiGiuseppe et al, 1996).

F) THROMBOCYTOPENIC PURPURA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Thrombotic thrombocytopenic purpura has been reported in 1 case. The reaction occurred 9 months after starting therapy (Holman et al, 1993).

G) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) TACROLIMUS

1) INCIDENCE/PEDIATRIC: Leukopenia with neutropenia was reported in 7 of 49 (14%) patients administered tacrolimus (Asante-Korang et al, 1996).
2) CASE REPORT: A 58-year-old man developed leukopenia (500 leukocytes/mL with 0% neutrophils) and thrombocytopenia 2 weeks after beginning tacrolimus therapy. A bone marrow biopsy showed severe hypoplasia of granulopoiesis and mild hypoplasia of megakaryogenesis. Within 2 weeks of discontinuing tacrolimus therapy, the patient's leukocyte count reached 7300 leukocytes/mL with 90% neutrophils (de-la-Serna-Higuera et al, 1997).

b) SIROLIMUS

1) Neutropenia was reported in 6 patients receiving allogeneic hematopoietic stem cell transplantation following the development of chronic graft-versus-host disease that were treated with sirolimus. Despite drug cessation, one patient developed persistent neutropenia which required a repeat marrow graft (Busca et al, 2005).

H) THROMBOSIS

1) WITH POISONING/EXPOSURE

a) Doses of greater than 25 mg temsirolimus may increase the risk of developing thrombosis (Prod Info TORISEL(TM) KIT IV injection, 2007).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) Flushing, itching (11% to 36%), and rash (8% to 24%) have been reported during tacrolimus therapy. (Prod Info PROGRAF(R) capsules, injection, 2005). Rash was reported in 47% of patients treated with temsirolimus (Prod Info TORISEL(TM) KIT IV injection, 2007).

B) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia has been associated with tacrolimus therapy in greater than 3% and less than 15% of patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

C) DRUG ACTION

1) WITH THERAPEUTIC USE

a) DERMAL ABSORPTION

1) An 11-month-old infant with severe cutaneous graft-versus-host disease received two applications of tacrolimus to his upper extremities and his serum levels rose to a toxic level of 23.4 ng/mL. No adverse clinical events were reported; however, blood levels rose again when topical administration was restarted (Prot-Labarthe et al, 2007).

D) NEOPLASM OF SKIN

1) WITH THERAPEUTIC USE

a) Patients receiving tacrolimus are at an increased risk of malignancies of the skin. The risk appears related to intensity and duration of therapy (Prod Info PROGRAF(R) capsules, injection, 2005).

Musculoskeletal

3.15.2)

A) DRUG-INDUCED MYOPATHY

1) WITH THERAPEUTIC USE

a) Arthralgia, leg cramps, myalgia, myasthenia and osteoporosis have been associated with tacrolimus therapy in greater than 3% of patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) Hyperglycemia has been reported during tacrolimus and temsirolimus administration (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015; Prod Info TORISEL(TM) KIT IV injection, 2007; Filler et al, 1997).
b) The incidence of new-onset diabetes mellitus requiring insulin replacement therapy in tacrolimus recipients is approximately 15% to 26% (Pham et al, 1996; Fung et al, 1991a).
c) Diabetogenic potential of tacrolimus is similar to cyclosporine (Starzl et al, 1991).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Anaphylaxis has been reported infrequently in patients receiving intravenous tacrolimus or temsirolimus (Prod Info TORISEL(TM) KIT IV injection, 2007; Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015). Intravenous tacrolimus contains castor oil which has been associated with anaphylaxis in other drugs containing castor oil derivatives (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

B) EOSINOPHIL COUNT RAISED

1) WITH THERAPEUTIC USE

a) EOSINOPHILIA was reported in 19 of 49 pediatric heart transplant patients treated with tacrolimus. Of the 19, 11 had allergic symptoms such as eczema, allergic rhinitis, asthma and non-infective sinusitis. Four of these patients also had elevated serum concentrations of IgE (Asante-Korang et al, 1996).

C) LYMPHOPROLIFERATIVE DISORDER

1) WITH THERAPEUTIC USE

a) CASE REPORT: A lymphoproliferative disorder was described in a 1 year-old boy after approximately 6 months of tacrolimus therapy. Lymph nodes and spleen in the child became smaller after discontinuance of tacrolimus, suggesting a potential etiological role (Frayha et al, 1991).
b) CASE REPORT: Two other cases of lymphoproliferative disorders have been reported in two pediatric patients receiving tacrolimus to prevent rejection following heart transplants. In one patient the lymphoproliferative disease resolved upon reducing the dose of tacrolimus while the second patient died of disseminated lymphoproliferative disease (Pham et al, 1996). Both cases developed 4 to 5 months after initiating tacrolimus therapy.

Reproductive

3.20.1)

A) TEMSIROLIMUS is classified as FDA pregnancy category D. EVEROLIMUS is classified as FDA pregnancy category C by the manufacturer of Zortress(R). SIROLIMUS and TACROLIMUS are classified as FDA pregnancy category C. Controlled studies in pregnant women are lacking. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. An increased incidence of malformations and developmental variations has been observed in rabbits given tacrolimus at doses greater than the maximum human daily dose. In rats and rabbits exposed to everolimus, embryofetal toxicities were observed. Tacrolimus is excreted in human milk. Everolimus is excreted in rat milk. In male rats, fertility was affected by exposure to everolimus.

3.20.2)

A) PLACENTAL BARRIER

1) Controlled studies in pregnant women are lacking. Tacrolimus has been shown to cross the placenta; the degree of transfer was not listed (Prod Info PROGRAF(R) oral capsules, IV injection, 2006).

B) LACK OF EFFECT

1) EVEROLIMUS

a) A 32-year-old woman with a transplanted kidney used everolimus throughout pregnancy and delivered a healthy infant at term (birth weight, 3020 grams; initial Apgar score, 9) without complications. The maintenance immunosuppression regimen included everolimus, cyclosporine, and corticosteroids. Monitoring included weekly fetal ultrasounds and maternal serum creatinine, proteinuria, and blood pressure, which were stable throughout gestation. Previous medical history included systemic lupus erythematous that remained in remission during and after the pregnancy (Carta et al, 2012).
b) A 30-year-old woman with a transplanted kidney delivered a healthy infant at 30 weeks' gestation with no congenital anomalies, despite a regimen of everolimus 0.75 mg twice daily, cyclosporine 100 mg twice daily, and corticosteroids 5 mg/day throughout the pregnancy. The patient was advised against pregnancy after an episode of acute rejection about 1 year after transplantation, which resolved with steroid therapy; the pregnancy was discovered at 12 weeks' gestation about 8 months later. The decision was made to continue with her current immunosuppressive regimen during the pregnancy. Imaging tests revealed no structural anomalies. Kidney function was stable (serum creatinine 2.1 mg/dL) until week 30, when the patient's renal function worsened (serum creatinine 3.86 mg/dL; proteinuria 1230 mg/day) and she developed severe hypertension (160/90 mmHg) with no peripheral edema. The 1280 g infant girl was delivered via cesarean section with an Apgar score of 10. The infant was continuing to develop normally at her 12-month followup (Veroux et al, 2011).

C) ANIMAL STUDIES

1) EVEROLIMUS

a) In animals, malformations (eg, sternal cleft) and retarded skeletal development, were reported at oral doses approximately 4% of the AUC of patients who receive the recommended 10 mg/day dose. These embryofetal toxicities occurred without maternal toxicity (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016; Prod Info Zortress(R) oral tablets, 2010).

2) TACROLIMUS

a) RABBITS: An increased incidence of malformations and developmental variations has been observed in rabbits given tacrolimus at doses greater than the maximum human daily dose (corrected for surface area) (Prod Info PROGRAF(R) oral capsules, IV injection, 2006).

3.20.3)

A) PREGNANCY CATEGORY

1) TACROLIMUS and SIROLIMUS are both classified by the manufacturers as FDA pregnancy category C (Prod Info PROGRAF(R) oral capsules, IV injection, 2006; Prod Info RAPAMUNE(R) oral solution, oral tablets, 2007).
2) TACROLIMUS: No adequate and/or well-controlled studies in pregnant women were available at the time of this review. However, the use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction (Prod Info PROGRAF(R) oral capsules, IV injection, 2006).
3) TEMSIROLIMUS is classified by the manufacturer as FDA pregnancy category D (Prod Info TORISEL(TM) KIT IV injection, 2007).

B) RISK SUMMARY

1) EVEROLIMUS

a) Do not give this drug to a pregnant woman. If pregnancy occurs, apprise patient of potential for fetal harm (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016).

C) CONTRACEPTION

1) EVEROLIMUS

a) Female patients of reproductive potential must use adequate contraception during treatment and for at least 8 weeks after discontinuation (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016).

D) LACK OF EFFECT

1) EVEROLIMUS

a) A 32-year-old woman with a transplanted kidney used everolimus throughout pregnancy and delivered a healthy infant at term (birth weight, 3020 grams; initial Apgar score, 9) without complications. The maintenance immunosuppression regimen included everolimus, cyclosporine, and corticosteroids. Monitoring included weekly fetal ultrasounds and maternal serum creatinine, proteinuria, and blood pressure, which were stable throughout gestation. Previous medical history included systemic lupus erythematous that remained in remission during and after the pregnancy (Carta et al, 2012).
b) A 30-year-old woman with a transplanted kidney delivered a healthy infant at 30 weeks' gestation with no congenital anomalies, despite a regimen of everolimus 0.75 mg twice daily, cyclosporine 100 mg twice daily, and corticosteroids 5 mg/day throughout the pregnancy. The patient was advised against pregnancy after an episode of acute rejection about 1 year after transplantation, which resolved with steroid therapy; the pregnancy was discovered at 12 weeks' gestation about 8 months later. The decision was made to continue with her current immunosuppressive regimen during the pregnancy. Imaging tests revealed no structural anomalies. Kidney function was stable (serum creatinine 2.1 mg/dL) until week 30, when the patient's renal function worsened (serum creatinine 3.86 mg/dL; proteinuria 1230 mg/day) and she developed severe hypertension (160/90 mmHg) with no peripheral edema. The 1280 g infant girl was delivered via cesarean section with an Apgar score of 10. The infant was continuing to develop normally at her 12-month followup (Veroux et al, 2011).

E) ANIMAL STUDIES

1) EVEROLIMUS

a) In animals, embryofetal toxicities, including increased resorption, preimplantation and postimplantation loss, decreased numbers of live fetuses were reported at oral doses approximately 4% of the AUC of patients who receive the recommended 10 mg/day dose. These embryofetal toxicities occurred without maternal toxicity. Offspring body weights were reduced up to 9% compared with controls and a slight reduction in offspring survival (about 5% died or missing) was also reported with everolimus doses of 0.1 mg/kg. However, there were no signs of maternal toxicity or adverse effects on delivery. There were no drug-related effects on developmental parameters (ie, morphological development, motor activity, learning, or fertility assessment) in the offspring. An increase in resorption was reported with oral doses approximately 1.6 times the 10-mg daily dose or the maximum human dose to treat subependymal giant cell astrocytoma [SEGA] on a body surface area basis; these effects occurred with maternal toxicity (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016; Prod Info Zortress(R) oral tablets, 2010).

2) TACROLIMUS

a) RABBITS: In rabbits, oral doses of 0.32 and 1 mg/kg during organogenesis resulted in maternal toxicity and an increased incidence of abortion (Prod Info PROGRAF(R) oral capsules, IV injection, 2006).
b) RATS: In rats, oral doses of 3.2 mg/kg during organogenesis caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability (Prod Info PROGRAF(R) oral capsules, IV injection, 2006).

3.20.4)

A) LACK OF INFORMATION

1) EVEROLIMUS, SIROLIMUS, TEMSIROLIMUS: At the time of this review, no data were available to assess the potential effects of exposure to these agents during lactation in humans (Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2014; Prod Info AFINITOR(R) oral tablets, 2014; Prod Info Zortress(R) oral tablets, 2010; Prod Info RAPAMUNE(R) oral solution, oral tablets, 2007; Prod Info TORISEL(TM) KIT IV injection, 2007).

B) BREAST MILK

1) TACROLIMUS: Tacrolimus has been shown to be excreted in human milk (Prod Info PROGRAF(R) oral capsules, IV injection, 2006), however, in only minimal amounts (maximum estimated weight-adjusted absorption 0.23% of maternal dose) (Bramham et al, 2013).
2) TACROLIMUS: An observational cohort study of 14 women who received tacrolimus during pregnancy and lactation, and their 15 infants, 11 of whom were exclusively breastfed, showed that the overall amounts of the drug to which breastfed infants are exposed are negligible. All infants who underwent serial blood sampling had tacrolimus levels that decreased by approximately 15% per day (ratio of geometric mean concentrations, 0.85; 95% CI, 0.82 to 0.88; p less than 0.001). Infants who were breastfed did not have higher tacrolimus blood concentrations compared with bottle-fed infants (median 1.3 mcg/L (range, 0 to 4) versus 1 mcg/L (range, 0 to 2.3); ratio of geometric mean concentrations, 0.93; 95% CI, 0.38 to 2.39; p=0.91). The estimated weight-adjusted infant dose, based on the maximum breast milk concentration of 1.56 mcg/L, is 0.56 mcg/L (equivalent to 0.23% of the maternal dose). Since the drug is present in breast milk in only minimal amounts, the authors suggest that women receiving tacrolimus who wish to breastfeed after appropriate advisement should not be discouraged from doing so, if monitoring of infant drug concentrations is available (Bramham et al, 2013).
3) EVEROLIMUS

a) It is not known whether everolimus is excreted in human milk (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016; Prod Info Zortress(R) oral tablets, 2010).
b) Do not breastfeed during treatment and for at least 2 weeks after discontinuation (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016).

C) ANIMAL STUDIES

1) EVEROLIMUS

a) In animal studies, everolimus and/or its metabolites were excreted into the milk of lactating animals at a concentration 3.5 times higher than in maternal serum (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016; Prod Info Zortress(R) oral tablets, 2010).

3.20.5)

A) EVEROLIMUS

1) Female fertility may be compromised by everolimus therapy, as menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone and follicle stimulating hormone have been reported in female patients who received everolimus (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016)

B) ANIMAL STUDIES

1) EVEROLIMUS

a) MALE RATS: In a 13-week male fertility study in rats, fertility was affected at AUC values 10% to 81% of the therapeutic exposure of patients who receive the everolimus 10 mg/day dose). Doses at 0.5 mg/kg and above affected testicular morphology; infertility occurred at doses 5 mg/kg with diminished plasma testosterone levels, sperm count, and sperm motility. Both doses fell within the range of therapeutic exposure (52 nanograms/hr/mL and 414 nanograms/hr/mL rat exposure, respectively, compared with 560 nanograms/hr/mL human exposure at 10 mg/day). The fertility index increased from zero (infertility) to 60% (12 of 20 mated females were pregnant) following a 10- to 13-week nontreatment period (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016; Prod Info Zortress(R) oral tablets, 2010).
b) FEMALE RATS: In female rats exposed to oral everolimus doses of at least 0.1 mg/kg (AUC values approximately 4% of the therapeutic exposure of patients who receive an everolimus 10 mg/day dose), there was an increase in preimplantation loss, suggesting that female fertility may be reduced with everolimus (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016; Prod Info Zortress(R) oral tablets, 2010).

Carcinogenicity

3.21.3)

A) LYMPHOMA-LIKE DISORDER

1) An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphomas and carcinomas of the skin (Prod Info Prograf(R), tacrolimus, 1994).

3.21.4)

A) SKIN TUMOR

1) A minimal incidence of skin tumors was determined in a 104-week dermal carcinogenicity study in mice administered tacrolimus ointment, 0.03% to 3% (equivalent to oral doses of 1.1 to 118 mg/kg/day or 3.3 to 354 mg/m(2)/day). In addition, no skin tumor formation was found under ambient room lighting with the topical application of tacrolimus (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2012).

B) LYMPHOMA

1) In a dermal carcinogenicity study, the incidence of pleomorphic lymphoma produced a statistically significant elevation with high doses of tacrolimus ointment, (0.03% to 3%; equivalent to oral doses of 1.1 to 118 mg/kg/day or 3.3 to 354 mg/m(2)/day), in high dose male (25/50) and female animals (27/50). In a mouse dermal carcinogenicity study, the incidence of undifferentiated lymphoma also demonstrated a statistically significant elevation with high doses in females (13/50). Lymphomas were observed at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment), and no drug-related tumors were noted with a dose of 1.1 mg/kg/day (0.03% tacrolimus ointment) (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2012).

C) LACK OF EFFECT

1) No relationship of tumor incidence to oral tacrolimus dosage was found in a 80-week carcinogenicity study in mice and in a 104-week study in rats. The highest doses used were 3 mg/kg/day (0.9 to 2.2 times the human clinical dose of 0.075 to 0.2 mg/kg/day based on AUC) in the mouse and 5 mg/kg/day (0.265 to 0.65 times the human clinical dose based on AUC) in the rat (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2012).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, including blood pressure. Monitor neurologic status.
B) Monitor CBC, urinalysis, liver enzymes and kidney function in patients following a significant overdose.
C) Monitor fluid status in patients that develop significant gastrointestinal symptoms (eg, vomiting, diarrhea).
D) Monitor serum electrolytes (including potassium, magnesium, glucose) following exposure.
E) Obtain a baseline ECG, continuous cardiac monitoring and serial ECGs following a significant exposure or as indicated.
F) Patients receiving these agents are at increased risk for serious infections including bacterial, viral, fungal and protozoal infections including opportunistic infections with therapeutic use. Obtain laboratory studies to determine the presence of infection and monitor for symptoms (ie, fever, chills, flu-like symptoms, etc) as indicated.

Methods

A)

1) High performance liquid chromatography with tandem mass spectrometry has been used for detection of sirolimus in blood with a sensitivity of 0.25 micrograms/liter (Mahalati & Kahan, 2001).
2) Liquid chromatography with ultraviolet detection has been used to specifically measure sirolimus in whole blood at a wavelength of 278 nanometers and has a reported sensitivity of 1.0 micrograms/liter (Mahalati & Kahan, 2001).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients demonstrating severe fluid and electrolyte imbalance should be admitted. Patients with persistent mental status changes and seizures should be admitted to an ICU setting.

6.3.1.2) HOME CRITERIA/ORAL

A) An asymptomatic adult with an inadvertent ingestion of 1 extra dose can be monitored at home. An asymptomatic child that ingests 1 dose can be monitored at home if reliable adult supervision is present. If the amount ingested is unknown the child should be observed in a healthcare facility.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult with a medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) All patients with a deliberate self-harm ingestion or inadvertent ingestion of more than 2 extra doses should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with an unintentional ingestion of more than 1 dose or an unknown amount should be observed in a healthcare facility until any symptoms resolve and adequate follow-up can be provided as needed.

Monitoring

A)

B)

C)

D)

E)

F)

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not indicated because CNS effects can develop and may include seizures.

6.5.2)

A) Consider activated charcoal if the exposure is recent, the patient is not vomiting or the airway can be protected.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive. Monitor vital signs and neurologic status. Monitor fluid status and electrolytes following significant vomiting and/or diarrhea. Administer oral or IV fluids and replace electrolytes as needed. Antidiarrheals may be indicated following persistent symptoms. Seizure activity may develop; treat with IV benzodiazepines, barbiturates. Mild hypertension usually does not require treatment.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment is symptomatic and supportive. Nitroprusside or nitroglycerin may be considered for significant or persistent hypertension. Monitor CBC with differential and monitor for signs of serious infection (eg, bacterial, viral, fungal, protozoal). Begin anti-infective treatment as soon as possible. Patients may also be at risk to develop anemia and thrombocytopenia. Transfuse packed red blood cells and platelets as indicated. Obtain a baseline ECG in patients (ie, preexisting congestive heart failure, bradyarrhythmias, antiarrhythmic medications) at risk to develop QT prolongation or as indicated.

B) MONITORING OF PATIENT

1) Monitor vital signs (including blood pressure) and neurologic status.
2) Monitor fluid status in patients that develop significant gastrointestinal symptoms (eg, vomiting, diarrhea).
3) Obtain serial CBC with differential and electrolytes (including potassium, magnesium, glucose) following a significant exposure.
4) Monitor renal function closely including serum creatinine, potassium, and urine output for signs and symptoms of nephrotoxicity.
5) Monitor liver enzymes after a significant overdose.
6) Obtain a baseline ECG, continuous cardiac monitoring and serial ECGs following a significant exposure or as indicated.
7) Patients receiving these agents are at increased risk for serious infections including bacterial, viral, fungal and protozoal infections including opportunistic infections with therapeutic use. Obtain laboratory studies to determine the presence of infection and monitor for symptoms (ie, fever, chills, flu-like symptoms, etc) as indicated.

C) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

D) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
3) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

4) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

8) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

9) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

10) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

11) PHENTOLAMINE/INDICATIONS

a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

12) PHENTOLAMINE/ADULT DOSE

a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

13) PHENTOLAMINE/PEDIATRIC DOSE

a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

14) PHENTOLAMINE/ADVERSE EFFECTS

a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

15) CAUTION

a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

E) PROLONGED QT INTERVAL

1) Monitor ECG carefully for dysrhythmias or QT interval prolongation. Although torsades de pointes has not bee reported with tacrolimus therapy, it may prolong the QT/QTc interval (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
2) Monitor electrolytes including calcium, magnesium and potassium. Correct any underlying electrolyte abnormalities.
3) Patients with underlying conditions (ie, congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that can lead to QT prolongation) may be at greatest risk (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

F) RENAL FAILURE SYNDROME

1) Monitor renal function closely including serum creatinine, potassium, and urine output (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015) for evidence of nephrotoxicity following a significant overdose.
2) DOPAMINE: Low-dose dopamine may be effective for the treatment of nephrotoxicity.

a) CASE REPORT: Low dose dopamine infusion, 2 mg/kg/minute, completely reversed cyclosporine-induced renal dysfunction in 8 healthy volunteers given 12 mg/kg orally. Dopamine had no effect on blood pressure or heart rate (Conte et al, 1989).

G) EXPERIMENTAL THERAPY

1) TACROLIMUS TOXICITY

a) METHYLPREDNISOLONE AND PHENYTOIN

1) CASE REPORT: A 9-year-old female renal transplant recipient developed tacrolimus toxicity (serum level 32 ng/mL (prior level was 4.9 ng/mL (target, 4 to 6 ng/mL)) after experiencing diarrhea and dehydration for 9 days prior to admission. The child appeared ill with evidence of dehydration (ie, drowsy, poor skin turgor, dry mucous membranes) and laboratory tests showed severe metabolic acidosis and acute renal injury (ie, elevated serum creatinine and urea). Tacrolimus was discontinued and she was started on IV methylprednisolone (2 mg/kg) and phenytoin (2 mg/kg) to increase the metabolism and clearance of tacrolimus as well as 3 fluid boluses of 20 mL/kg. Within 24 hours, the patient was more alert and her tacrolimus level had decreased to approximately 11 ng/mL. She was restarted on tacrolimus at 1.25 mg twice daily and needed ongoing therapy for dehydration but recovered completely (Bax et al, 2014). Its suggested that these agents accelerate the drug clearance of tacrolimus through the induction of CYP3A4.

b) PHENOBARBITAL

1) CASE REPORT: A 4-month-old infant, who was a liver transplant recipient, experienced elevations in her whole-blood tacrolimus levels, peaking at 49 ng/mL, and apparently coinciding with renal function impairment. Intravenous administration of phenobarbital, 5 mg/kg daily in two divided doses, resulted in a progressive decrease of whole-blood tacrolimus levels to 7.7 ng/mL, accompanied by an increase in urine output (McLaughlin et al, 2000). It is believed that phenobarbital administration increased the clearance of tacrolimus by inducing hepatic oxidases.

c) ADENOSINE RECEPTOR ANTAGONISTS

1) ANIMAL DATA: In a study of Sprague Dawley rats given an acute toxic tacrolimus dose, a selective adenosine(3) {A3} receptor antagonist administered intraperitoneally was found to improve glomerular filtration rate without promoting sodium excretion. The authors suggested it may be renoprotective following acute tacrolimus-induced nephropathy. Further research is indicated to determine its safe use in the clinical setting (McLaughlin et al, 2006).

Enhanced Elimination

A)

1) HEMODIALYSIS: Based on the high protein binding of these agents, hemodialysis is not anticipated to be effective following overdose (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015; Prod Info AFINITOR(R) oral tablets, 2014; Prod Info RAPAMUNE(R) oral solution, oral tablets, 2007).

Abstracts

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) EVEROLIMUS

a) MALIGNANCY

1) ORAL: The recommended dose for the treatment of advanced hormone receptor-positive HER2-negative breast cancer, advanced renal cell carcinoma, progressive neuroendocrine tumors of pancreatic, GI, or lung origin, and renal angiomyolipoma with tuberous sclerosis complex is 10 mg daily; do not crush or chew the tablet. The dose may be reduced to 5 mg daily if unable to tolerate secondary to adverse effects (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016).
2) ORAL: The recommended dose for the treatment of subependymal giant cell astrocytoma is 4.5 mg/m(2) once daily. Adjustments are made according to tumor volume, whole blood trough concentrations, and tolerability (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016).

b) ORGAN TRANSPLANT PROPHYLAXIS

1) KIDNEY: The recommended dose is oral everolimus 0.75 mg twice daily in combination with reduced dose cyclosporine beginning as soon as possible after transplantation (Prod Info ZORTRESS(R) oral tablets, 2013).
2) LIVER: The recommended dose is oral everolimus 1 mg twice daily in combination with reduced dose tacrolimus. Do not begin treatment until at least 30 days after transplantation (Prod Info ZORTRESS(R) oral tablets, 2013).

2) PIMECROLIMUS

a) TOPICAL: A 1% cream has been topically applied twice daily to treat atopic dermatitis and chronic irritant contact dermatitis, and a 0.6% cream has been used topically to treat allergic contact dermatitis (Wellington & Spencer, 2000; Smith, 2000).

3) SIROLIMUS

a) ORAL: A loading dose of 6 mg with a daily maintenance dose of 2 mg is recommended for use in renal transplant patients (Prod Info RAPAMUNE(R) oral solution, oral tablets, 2015).
b) For de novo transplant recipients a loading dose corresponding to 3 times the maintenance dose should be given (ie, a daily maintenance dose of 2 mg preceded by a loading dose of 6 mg). Drug monitoring should be performed to maintain sirolimus drug concentrations within the target-range (Prod Info RAPAMUNE(R) oral solution, oral tablets, 2015).

4) TACROLIMUS

a) IMMEDIATE-RELEASE

1) ORAL

a) ADULT KIDNEY TRANSPLANT: INITIAL: 0.2 mg/kg/day given in 2 divided doses (every 12 hours) in combination with azathioprine; 0.1 mg/kg/day in combination with mycophenolate mofetil/interleukin-2-receptor antagonist (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
b) LIVER TRANSPLANT: INITIAL: 0.1 to 0.15 mg/kg/day given in 2 divided doses (every 12 hours) (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
c) HEART TRANSPLANT: INITIAL: 0.075 mg/kg/day given in 2 divided doses (every 12 hours) (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).

2) INTRAVENOUS

a) The recommended Prograf(R) starting dose is 0.03 to 0.05 mg/kg/day as a continuous infusion starting at least 6 hours after transplantation (Prod Info PROGRAF(R) oral capsules, IV injection, 2011).

1) If converting from IV to oral, wait at least 8 to 12 hours after discontinuing the IV infusion; switch to oral therapy as soon as tolerated (Prod Info PROGRAF(R) oral capsules, IV injection, 2011).

b) Adjunctive adrenal corticosteroid therapy is recommended early posttransplant (Prod Info PROGRAF(R) oral capsules, IV injection, 2011).

3) TOPICAL

a) For second-line treatment of moderate-to-severe atopic dermatitis, apply a thin layer of 0.03% or 0.1% ointment topically to affected areas twice daily (Prod Info Protopic(R), 2006).

b) EXTENDED-RELEASE

1) TABLETS: INITIAL DOSE: Administer 80% of prior immediate-release dose orally once daily (Prod Info ENVARSUS XR(R) oral tablets, 2015).
2) TABLETS: TITRATION AND MAINTENANCE DOSE: Adjust dose to achieve target trough concentration of 4 to 11 nanograms/mL based on at least 2 measurements on separate days during the first week following transition to extended-release tablets and after any changes in dosage, renal or hepatic function, or concomitant use of CYP3A4 inducers or inhibitors (Prod Info ENVARSUS XR(R) oral tablets, 2015).
3) CAPSULES: INITIAL: With mycophenolate mofetil, steroids, and basiliximab induction, 0.15 to 0.2 mg/kg orally prior to reperfusion or within 48 hours of transplant; with mycophenolate mofetil and steroids without basiliximab induction, 0.1 mg/kg for first dose (preoperative) and 0.2 mg/kg for second dose (postoperative) (Prod Info ASTAGRAF XL(R) oral extended-release capsules, 2015).
4) CAPSULES: TITRATION AND MAINTENANCE DOSE: Adjust dose to achieve target trough concentration of 5 to 15 nanograms/mL (Prod Info ASTAGRAF XL(R) oral extended-release capsules, 2015).

5) TEMSIROLIMUS

a) INTRAVENOUS: The recommended dose for advanced cell carcinoma is 25 mg infused over a 30- to 60-minute period once a week with a continuation of treatment until disease progression or unacceptable toxicity occurs (Prod Info TORISEL(R) intravenous injection, 2012).

1) Patients should be premedicated with 25 to 50 mg of diphenhydramine (or a similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus (Prod Info TORISEL(R) intravenous injection, 2012).
2) Monitor blood counts. Hold temsirolimus if the absolute neutrophil count is less than 1,000/mm(3), platelet count is less than 75,000/mm(3), or in the presence of grade 3 or greater adverse events (Prod Info TORISEL(R) intravenous injection, 2012).

7.2.2)

A) SPECIFIC SUBSTANCE

1) TACROLIMUS

a) IMMEDIATE-RELEASE

1) INTRAVENOUS

a) The recommended Prograf(R) starting dose is 0.03 to 0.05 mg/kg/day as a continuous IV infusion (Prod Info PROGRAF(R) oral capsules, IV injection, 2011).

1) The initial dose of tacrolimus should be administered NO SOONER than 6 hours after liver transplantation (Prod Info PROGRAF(R) oral capsules, IV injection, 2011).
2) Concomitant corticosteroid therapy is recommended early posttransplantation (Prod Info PROGRAF(R) oral capsules, IV injection, 2011).
3) Continuous intravenous infusion should be continued only until the patient can tolerate oral administration of tacrolimus capsules (Prod Info PROGRAF(R) oral capsules, IV injection, 2011).

2) ORAL

a) LIVER TRANSPLANT: The recommended oral starting dose for tacrolimus is 0.15 to 0.2 mg/kg/day administered in 2 divided daily doses every 12 hours for pediatric liver transplant patients (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
b) HEART OR KIDNEY TRANSPLANTATION: Experience in the pediatric setting for these transplants is limited (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
c) (Astagraf XL(TM) with basiliximab induction) for pediatric kidney transplant patients 16 years or older, the initial recommended dose is 0.15 mg/kg/day orally once daily in morning, administer prior to or within 48 hours of transplantation to initiate therapy, may delay until renal function has recovered; titrate dose based on clinical response, whole blood levels, and tolerability (Prod Info ASTAGRAF XL(TM) oral extended-release capsules, 2013).
d) (Astagraf XL(TM) without induction) for pediatric kidney transplant patients 16 years of older, the recommended preoperative dose is 0.1 mg/kg/day orally once, administer within 12 hours of reperfusion; recommended postoperative dosing, 0.2 mg/kg/day orally once daily in the morning; administer first dose not less than 4 hours after the preoperative dose and within 12 hours of reperfusion; titrate dose based on clinical response, whole blood levels, and tolerability (Prod Info ASTAGRAF XL(TM) oral extended-release capsules, 2013).

3) TOPICAL

a) 2 years or older, apply thin layer of 0.03% ointment topically to affected areas twice daily (Prod Info Protopic(R), 2006).

b) EXTENDED-RELEASE

1) The safety and efficacy of tacrolimus in pediatric patients have not been established (Prod Info ENVARSUS XR(R) oral tablets, 2015).

2) EVEROLIMUS

a) ORAL: The recommended dose in pediatric patients 1 year of age or older for the treatment of subependymal giant cell astrocytoma is 4.5 mg/m(2) once daily. Adjustments are made according to tumor volume, whole blood trough concentrations, and tolerability (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016).
b) The safety and efficacy of everolimus in pediatric patients below the age of 1 year with subependymal giant cell astrocytoma have not been established (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) DISPERZ oral tablets for suspension, 2016).
c) The safety and efficacy of everolimus in pediatric patients with advanced renal cell carcinoma, progressive neuroendocrine tumors of pancreatic, GI, or lung origin, or renal angiomyolipoma with tuberous sclerosis complex have not been established (Prod Info AFINITOR(R) oral tablets, 2016; Prod Info AFINITOR(R) oral tablets, 2016).

3) SIROLIMUS

a) The safety and efficacy of sirolimus in pediatric patients below the age of 13 years or in pediatric renal transplant patients considered to be at high immunologic risk have not been established (Prod Info RAPAMUNE(R) oral solution, oral tablets, 2015).

4) TEMSIROLIMUS

a) The efficacy of temsirolimus in pediatric patients has not been established (Prod Info TORISEL(R) intravenous injection, 2012).
b) Limited data are available regarding use of temsirolimus in pediatric patients. Temsirolimus was studied in 71 pediatric patients (age 1 to 17 years, n=59; age 18 to 21 years, n=12) with advanced recurrent or refractory solid tumors (ie, neuroblastoma, rhabdomyosarcoma, or high grade glioma) during a phase 1 to 2 study using a dosage range of 10 to 150 mg/m(2) as a 60 minute infusion once weekly in 3 week cycles (Prod Info TORISEL(R) intravenous injection, 2012).

Minimum Lethal Exposure

A)

1) TACROLIMUS: No deaths in humans have been reported as a result of a tacrolimus overdose.

B)

1) ADULT RATS: Death was observed at 52 times or greater the human oral dose and 16 times the human intravenous dose (based on body surface area corrections) (Prod Info PROGRAF(R) capsules, injection, 2005).
2) IMMATURE RATS: Death was observed at 16 times or greater the human oral dose and 16 times the human intravenous dose (based on body surface area corrections) (Prod Info PROGRAF(R) capsules, injection, 2005).

Maximum Tolerated Exposure

A)

1) ROUTE OF ADMINISTRATION

a) ORAL: Acute overdosages of up to 30 times the therapeutic dose have occurred and most patients have remained asymptomatic and recovered completely. Clinical events that did develop (ie, tremors, abnormal renal function, hypertension, and peripheral edema) were similar to effects reported with therapy (Prod Info PROGRAF(R) oral capsules, intravenous injection, 2015).
b) INTRAVENOUS: 0.2 mg/kg/day in adults (Venkataramanan et al, 1990).

1) CASE REPORT: A 42-year-old, healthy woman developed metabolic acidosis and non-oliguric renal failure after inadvertently receiving an estimated daily dose of 2.1 mg/kg/day of tacrolimus IV over 4 days. The patient recovered completely following supportive care. Although the development of renal failure may have been multifactorial (ie, history of hypertension with ACE inhibitor use and recent IV contrast), the authors concluded that the patient's rapid response to therapy was consistent with an acute tacrolimus exposure (O'Connor et al, 2008).

2) CASE REPORTS

a) PEDIATRIC

1) LACK OF EFFECT

a) INGESTION: An 18 month-old boy was found playing with a bottle of tacrolimus and potentially ingested 90 mg (8 mg/kg) and was brought to the ED an hour later. He was alert with a normal physical exam and vital signs. Cardiac monitoring was initiated and the patient remained in normal sinus rhythm. He was given 11 g of activated charcoal and was admitted for observation. All laboratory studies were within normal limits. A serum tacrolimus concentration 5 hours after exposure was 7.5 mcg/L and was 2.7 mcg/L about 36 hours after exposure (Kessler et al, 2015).
b) INGESTION: Two, 2-year-old girls (each approximately 11 kg) ingested 10 and 11 mg, respectively, of tacrolimus. Both remained asymptomatic; laboratory values were obtained in one child and remained normal (Mrvos et al, 1997).
c) TOPICAL: An 11-month-old infant with severe cutaneous graft-versus-host disease received 2 applications of tacrolimus to his upper extremities and his serum levels rose to 23.4 ng/mL. No adverse clinical events were reported (Prot-Labarthe et al, 2007).

b) ADULT

1) LACK OF EFFECT OR MINOR EVENTS

a) A 20-year-old woman intentionally ingested 41 mg tacrolimus and developed minor symptoms of nausea, vomiting, and headache. Blood tacrolimus concentration was 42.6 ng/mL (normal 9.8 to 19.4 ng/mL). No further symptoms were observed and the patient was discharged to home after 48 hours (Su et al, 2002).
b) A 59-year-old man inadvertently received twice-daily dose of 5 mg tacrolimus (instead of 0.5 mg) for 8 days and developed minor signs and symptoms of toxicity. The patient had a blood tacrolimus concentration of 118.5 ng/mL on admission with a trough blood level above 90 ng/mL for over a week. By day 6, his tacrolimus level was 9.8 ng/mL (Hardwick & Batiuk, 2002).
c) A 23-year-old woman coingested 375 mg of tacrolimus and 20 glipizide (5 mg) tablets. Hypoglycemia was the only adverse effect reported (Mrvos et al, 1997).
d) A 29-year-old man intentionally ingested 90 mg (1.5 mg/kg) of tacrolimus. Despite an initially elevated creatinine (peaked at 3.9 mg/dL), the patient had no other adverse effects (Mrvos et al, 1997).
e) A 36-year-old man was prescribed 0.2 mg/kg of tacrolimus orally in 2 divided doses and instead was inadvertently given a single oral dose of 60 mg (1 mg/kg). The patient remained asymptomatic during the observation period following the overdose (Yeh et al, 1999).

B)

1) During sirolimus clinical trials, 2 patients received overdose ingestions of 120 mg and 150 mg, respectively. The patient who ingested 150 mg of sirolimus developed transient atrial fibrillation, but the patient who ingested 120 mg of sirolimus remained asymptomatic (Prod Info Rapamune(R), sirolimus, 1999).
2) An observational study was conducted to assess the possible clinical outcomes following a sirolimus overdose. Of the 5 cases, 3 occurred accidentally in young children and 2 in adults (an administration error in one case and suicide intent in the other). The highest dose ingested was 103 mg in an 18-year-old girl who presented 24 hours after the exposure. Decontamination was not performed and the patient's only complaint was tiredness. Her liver function and complete blood count remained normal but an increase in her total cholesterol occurred with a normal triglyceride level. A minor dosing error occurred with the other adult but no symptoms developed. The 3 children ranged in age from almost 2 to 3 years-old and two remained asymptomatic. A 2.5 year-old boy ingested 3 mg and received a dose of activated charcoal 4 hours after exposure. He developed a mild fever and gastroenteritis and had an increase in alkaline phosphatase that were likely related to the overdose. He recovered completely (Ceschi et al, 2015).

C)

1) During clinical trials with cancer patients repeated intravenous doses as high as 220 mg/m(2) were given. The manufacturer has suggested that doses of greater than 25 mg may result in an increased risk of developing thrombosis, bowel perforation, interstitial lung disease, seizures and psychosis (Prod Info TORISEL(TM) KIT IV injection, 2007).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Trough tacrolimus blood levels, determined during the second week to one year post-transplantation of a US clinical trial, ranged from 9.8 to 19.4 nanograms/mL(Prod Info Prograf(R), tacrolimus, 1994).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) ADULT

1) SUMMARY

a) Based on several case reports in adults, overdoses resulting in elevated tacrolimus concentrations have exhibited minimal or no toxicity (Hardwick & Batiuk, 2002; Su et al, 2002; Mrvos et al, 1997; Mrvos et al, 1997).

2) ORAL EXPOSURE

a) A 42-year-old, healthy woman developed metabolic acidosis and non-oliguric renal failure after inadvertently receiving an estimated daily dose of 2.1 mg/kg/day of tacrolimus over 4 days. Her tacrolimus concentration was 96.8 ng/L (target trough concentrations are usually between 5 to 25 ng/mL), approximately 27 hours after the last dose. The patient had an elimination half-life of 16.5 hours as compared to a mean half-life of 34.2 hours reported in healthy volunteers; this finding could not be clearly explained. At discharge on day 4, the patient had normal laboratory values (O'Connor et al, 2008).
b) A 59-year-old man inadvertently received twice-daily dose of 5 mg tacrolimus (instead of 0.5 mg) for 8 days and developed minor signs and symptoms of toxicity. The patient had a blood tacrolimus concentration of 118.5 ng/mL on admission with a trough blood level above 90 ng/mL for over a week. By day 6, his tacrolimus level was 9.8 ng/mL (Hardwick & Batiuk, 2002).
c) A tacrolimus serum level of 42.6 ng/mL was reported in a 20-year-old female, who complained of nausea, vomiting, and headache, but had normal vital signs following an intentional ingestion of approximately 41 mg of tacrolimus (Su et al, 2002).
d) A 23-year-old female coingested 375 mg of tacrolimus and twenty 5 mg glipizide tablets. Plasma tacrolimus level peaked within 24 hours (following admission) at 11.4 ng/mL (therapeutic 0.2 to 6 ng/mL). Although hypoglycemia was present on admission, the patient developed no further symptoms (Mrvos et al, 1997).
e) A 29-year-old male initially had an elevated creatinine level (3.9 mg/dL) but, remained asymptomatic following an ingestion of 90 mg of tacrolimus. A peak serum level of 8.5 ng/mL (therapeutic, 0.2 to 6 ng/mL) 12 hours after admission was reported (Mrvos et al, 1997).

3) DERMAL ABSORPTION

a) CASE REPORTS: A 62-year-old woman underwent allogeneic bone marrow transplantation and developed chronic graft-versus-host disease (GVHD). She had erythematous with desquamative areas that covered at least 70% of her body surface area and was treated with oral corticosteroids and tacrolimus and topical tacrolimus 0.1% ointment twice daily. To improve the effectiveness of the topical application, occlusive dressings were applied over the ointment. After 6 days, her tacrolimus trough level reached 23 ng/mL (normal, 5 to 15 ng/mL); prior to admission her tacrolimus level was subtherapeutic (2 ng/mL). Her oral tacrolimus dose was decreased but her tacrolimus level continued to rise making it necessary to discontinue the occlusive dressings. No adverse events related to the elevated tacrolimus levels were observed (Olson et al, 2014).

1) In a similar case, a 25-year-old man who underwent an allogeneic bone marrow transplant also developed severe dermal GVHD with erythematous papules covering his entire body. Despite other treatments, he was admitted and treated with IV corticosteroids, topical tacrolimus twice daily, and other topical creams/lotions. Prior to starting occlusive dressings, the patient's tacrolimus trough level was 7.1 ng/mL. Two days after starting occlusive dressing therapy his trough level was 22.1 ng/mL; no other laboratory or treatment changes were reported. Although his skin was improving, the dressings were stopped due to increased tacrolimus levels. No adverse events related to the elevated tacrolimus levels were observed (Olson et al, 2014).

b) PEDIATRIC

1) DERMAL ABSORPTION: An 11-month-old infant with severe cutaneous graft-versus-host disease received two applications of tacrolimus to his upper extremities and his serum level rose to a toxic level of 23.4 ng/mL. No adverse clinical events were reported; however, blood levels rose again when topical administration was restarted (Prot-Labarthe et al, 2007).

Toxicity Information

7.7.1)

A) SIROLIMUS

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 597 mg/kg ((RTECS, 2000))

2) LD50- (ORAL)MOUSE:

a) greater than 2500 mg/kg ((RTECS, 2000))

3) LD50- (INTRAPERITONEAL)RAT:

a) 18220 mcg/kg ((RTECS, 2000))

B) TACROLIMUS

1) LD50- (INTRAPERITONEAL)MOUSE:

a) greater than 200 mg/kg (Budavari, 1996)

2) LD50- (ORAL)RAT:

a) 134 mg/kg (Budavari, 1996)

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TACROLIMUS AND RELATED AGENTS

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General Bibliography