Torisel

Do not eat grapefruit or drink grapefruit juice while taking this medication.

If you miss an appointment to receive a dose of temsirolimus, call your doctor right away.

The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label [see WARNINGS AND PRECAUTIONS].

• Hypersensitivity/Infusion Reactions [see WARNINGS AND PRECAUTIONS]
• Hepatic Impairment [see WARNINGS AND PRECAUTIONS]
• Hyperglycemia/Glucose Intolerance [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Interstitial Lung Disease [see WARNINGS AND PRECAUTIONS]
• Hyperlipemia [see WARNINGS AND PRECAUTIONS]
• Bowel Perforation [see WARNINGS AND PRECAUTIONS]
• Renal Failure [see WARNINGS AND PRECAUTIONS]
• Wound Healing Complications [see WARNINGS AND PRECAUTIONS]
• Intracerebral Hemorrhage [see WARNINGS AND PRECAUTIONS]

The most common (≥30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN-α weekly [see Clinical Studies].

Treatment with the combination of TORISEL 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.

Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TORISEL 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:

Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial

The following selected adverse reactions were reported less frequently (<10%).

Gastrointestinal Disorders – Gastrointestinal hemorrhage (1%), rectal hemorrhage (1%).

Eye Disorders – Conjunctivitis (including lacrimation disorder) (8%).

Immune System – Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received TORISEL and ACE inhibitors concomitantly.

Infections – Pneumonia (8%), upper respiratory tract infection (7%), wound infection/postoperative wound infection (1%), sepsis (1%).

General Disorders and Administration Site Conditions -Diabetes mellitus (5%).

Respiratory, Thoracic and Mediastinal Disorders – Pleural effusion (4%).

Vascular – Hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%), thrombophlebitis (1%), pericardial effusion (1%).

Nervous System Disorders – Convulsion (1%).

Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial

Post-Marketing And Other Clinical Experience

The following adverse reactions have been identified during post approval use of TORISEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been observed in patients receiving temsirolimus: rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome (reflex sympathetic dystrophy), pancreatitis, cholecystitis, and cholelithiasis.

There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.

You should not use temsirolimus if you have severe liver disease.

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma1 2 12 (designated an orphan drug by FDA for this use);17 considered to be a first-line therapy in poor-risk patients.2 10 13 14 20

Also has been studied in combination with interferon alfa to treat advanced renal cell carcinoma†.1 2 19 Results from a randomized study indicate overall survival benefit with temsirolimus alone compared with interferon alfa alone.1 2 Combination therapy with interferon alfa and temsirolimus also did not result in improved overall survival compared with interferon alfa alone.1 2

Both temsirolimus and its principal active metabolite, sirolimus, metabolized principally by CYP3A4.1 6 16 18 20 .1 6 16 18 Temsirolimus inhibits CYP isoenzymes 2D6 and 3A4 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of the principal active metabolite sirolimus).1 Avoid concomitant use with potent CYP3A4 inhibitors; if no alternative is available, consider temsirolimus dosage adjustment.1 (See Specific Drugs and Foods under Interactions.)

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of the principal active metabolite sirolimus).1 Avoid concomitant use with potent CYP3A4 inducers; if no alternative is available, consider temsirolimus dosage adjustment.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6 and CYP3A4: No evidence of clinically important effects in drug interaction studies with substrates of CYP2D6; no effect anticipated on substrates of CYP3A4.1

Specific Drugs and Foods

• If you need to store Torisel at home, talk with your doctor, nurse, or pharmacist about how to store it.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Torisel or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Torisel. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

The following serious adverse reactions have been associated with Torisel in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions (5)].

• Hypersensitivity/Infusion Reactions [see Warnings and Precautions (5.1)]
• Hepatic Impairment [see Warnings and Precautions (5.2)]
• Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3)]
• Infections [see Warnings and Precautions (5.4)]
• Interstitial Lung Disease [see Warnings and Precautions (5.5)]
• Hyperlipidemia [see Warnings and Precautions (5.6)]
• Bowel Perforation [see Warnings and Precautions (5.7)]
• Renal Failure [see Warnings and Precautions (5.8)]
• Wound Healing Complications [see Warnings and Precautions (5.9)]
• Intracerebral Hemorrhage [see Warnings and Precautions (5.10)]

The most common (≥30%) adverse reactions observed with Torisel are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with Torisel are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, Torisel alone, and Torisel and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received Torisel 25 mg weekly, and 208 patients received a combination of Torisel and IFN-α weekly [see Clinical Studies (14)].

Treatment with the combination of Torisel 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone.

Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received Torisel 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison:

The following selected adverse reactions were reported less frequently (<10%).

Gastrointestinal Disorders – Gastrointestinal hemorrhage (1%), rectal hemorrhage (1%).

Eye Disorders – Conjunctivitis (including lacrimation disorder) (8%).

Immune System – Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received Torisel and ACE inhibitors concomitantly.

Infections – Pneumonia (8%), upper respiratory tract infection (7%), wound infection/post-operative wound infection (1%), sepsis (1%).

General Disorders and Administration Site Conditions - Diabetes mellitus (5%).

Respiratory, Thoracic and Mediastinal Disorders – Pleural effusion (4%).

Vascular – Hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%), thrombophlebitis (1%), pericardial effusion (1%).

Nervous System Disorders – Convulsion (1%).

Post-marketing and Other Clinical Experience

The following adverse reactions have been identified during post approval use of Torisel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been observed in patients receiving temsirolimus: angioedema, rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome (reflex sympathetic dystrophy), pancreatitis, cholecystitis, and cholelithiasis.

There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.

Temsirolimus, an inhibitor of mTOR, is an antineoplastic agent.

Temsirolimus is a white to off-white powder with a molecular formula of C56H87NO16 and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of pH.

The chemical name of temsirolimus is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23, 27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 4'-[2,2-bis(hydroxymethyl)propionate]; or Rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate].

Torisel (temsirolimus) injection, 25 mg/mL, is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile solution. Torisel (temsirolimus) injection requires two dilutions prior to intravenous infusion. Torisel (temsirolimus) injection should be diluted only with the supplied DILUENT for Torisel.

DILUENT for Torisel is a sterile, non-aqueous solution that is supplied with Torisel injection, as a kit.

Torisel (temsirolimus) injection, 25 mg/mL:

Active ingredient: temsirolimus (25 mg/mL)

Inactive ingredients: dehydrated alcohol (39.5% w/v), dl-alpha-tocopherol (0.075% w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v).

DILUENT for Torisel:

Inactive ingredients: polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v).

After the Torisel (temsirolimus) injection vial has been diluted with DILUENT for Torisel, in accordance with the instructions in section 2.5, the solution contains 35.2% alcohol.

Torisel (temsirolimus) injection and DILUENT for Torisel are filled in clear glass vials with butyl rubber stoppers.

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. (2006) 63:1172–1193.
4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Torisel (temsirolimus) is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Torisel is used to treat cancer of the kidneys, also called renal cell carcinoma.

Torisel may also be used for purposes not listed in this medication guide.

You should not use Torisel if you are allergic to temsirolimus, or if you have:

• severe liver disease.

To make sure Torisel is safe for you, tell your doctor if you have ever had:

• liver disease;

• kidney disease;

• high cholesterol or triglycerides (a type of fat in the blood);

• diabetes;

• a head injury, stroke, or brain tumor; or

• an allergy to sirolimus (Rapamune).

Torisel can harm an unborn baby. Use effective birth control to prevent pregnancy while you are using this medicine, whether you are a man or a woman. Torisel use by either parent may cause birth defects.

Keep using birth control for at least 3 months after your last dose of Torisel. Tell your doctor right away if a pregnancy occurs while either the mother or the father is using temsirolimus.

It is not known whether temsirolimus passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Usual Adult Dose for Renal Cell Carcinoma:

25 mg IV infusion over a 30 to 60 minute period once a week
Duration of therapy: Treat until disease progression or unacceptable toxicity

Comments: IV diphenhydramine 25 to 50 mg (or similar antihistamine) should be given approximately 30 minutes before the start of each dose

Use: Advanced renal cell carcinoma

Call your doctor if you miss an appointment for your Torisel injection.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Do not receive a "live" vaccine while using Torisel, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Grapefruit and grapefruit juice may interact with temsirolimus and lead to unwanted side effects. Avoid the use of grapefruit products while taking Torisel.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Applies to temsirolimus: intravenous solution

Hepatic

Very common (10% or more): Increased AST (up to 38%)
Common (1% to 10%): Increased total bilirubin, increased ALT[Ref]

Immunologic

Very common (10% or more): Bacterial and viral infections (including abscess, bronchitis, cellulitis, herpes simplex, oral herpes, herpes zoster; up to 28.3%)
Common (1% to 10%): Sepsis, candidiasis, fungal infection, flu syndrome[Ref]

Hypersensitivity

Common (1% to 10%): Allergic/hypersensitivity reactions[Ref]

Respiratory

Very common (10% or more): Dyspnea (up to 28%), cough (up to 29%), epistaxis (up to 21.5%), pharyngitis (up to 12%), pneumonia (up to 10.9%), rhinitis (up to 10%)
Common (1% to 10%): Upper respiratory tract infection, pleural effusion, sinusitis, interstitial lung disease/pneumonitis (including fatalities)
Uncommon (0.1% to 1%): Laryngitis
Postmarketing reports: Pneumocystis jiroveci pneumonia[Ref]

Renal

Very common (10% or more): Increased creatinine (up to 57%)
Common (1% to 10%): Renal failure[Ref]

Hematologic

Very common (10% or more): Decreased hemoglobin (up to 94%), decreased lymphocytes (up to 53%), anemia (up to 41.1%), decreased platelets (up to 40%), decreased leukocytes (up to 32%), thrombocytopenia (up to 30.2%), decreased neutrophils (up to 19%), neutropenia (up to 14.3%)
Common (1% to 10%): Leukopenia, lymphopenia[Ref]

Cardiovascular

Very common (10% or more): Chest pain (up to 16%)
Common (1% to 10%): Hypertension, venous thromboembolism (including deep vein thrombosis and pulmonary embolism, some fatal), thrombophlebitis, pericardial effusion[Ref]

Dermatologic

Very common (10% or more): Rash (including eczema, exfoliative dermatitis, maculopapular rash, pustular rash, vesiculobullous rash; up to 47%), pruritus (up to 21.5%), nail disorder (up to 14%), dry skin (up to 11%), acne (up to 10%)
Common (1% to 10%): Folliculitis, ecchymosis, petechiae
Postmarketing reports: Stevens-Johnson syndrome[Ref]

Other

Very common (10% or more): Asthenia (up to 51%), fatigue (up to 41.4%), edema (including facial and peripheral; up to 38%), pyrexia (up to 28.3%), pain (up to 28%)
Common (1% to 10%): Wound infection/post-operative wound infection, impaired wound healing
Postmarketing reports: Angioneurotic edema-type reactions, extravasations[Ref]

Endocrine

Very common (10% or more): Increased glucose (up to 89%), hyperglycemia (up to 26%)
Common (1% to 10%): Diabetes mellitus[Ref]

Gastrointestinal

Very common (10% or more): Mucositis (including stomatitis, glossitis, mouth ulceration; up to 41%), nausea (up to 37%), diarrhea (up to 34%), abdominal pain (up to 21%), constipation (up to 20%), vomiting (up to 19%)
Common (1% to 10%): Bowel perforation (including fatal cases), gastrointestinal hemorrhage, rectal hemorrhage, gastritis, dysphagia, abdominal distension, oral pain, gingivitis, mouth pain, oral moniliasis, hemorrhoidal hemorrhage
Uncommon (0.1% to 1%): Intestinal/duodenal perforation, lip hemorrhage, mouth hemorrhage[Ref]

Genitourinary

Very common (10% or more): Unspecified urogenital adverse reaction (up to 30%), urinary tract infection (including cystitis, dysuria, hematuria, urinary frequency; up to 15%)[Ref]

Metabolic

Very common (10% or more): Increased total cholesterol (up to 87%), increased triglycerides (up to 83%), increased alkaline phosphatase (up to 68%), decreased phosphorus (up to 49%), decreased calcium (up to 39%), decreased appetite (up to 33.3%), anorexia (up to 32%), hyperlipidemia (up to 27%), decreased potassium (up to 21%), weight loss (up to 19%), hypercholesterolemia (up to 18.8%), hypertriglyceridemia (up to 17.4%), hypokalemia (up to 13.7%), increased lactic dehydrogenase (up to 11%)
Common (1% to 10%): Dehydration, hypocalcemia, hypophosphatemia[Ref]

Musculoskeletal

Very common (10% or more): Back pain (up to 20%), arthralgia (up to 18%), muscle cramp (up to 12%)
Common (1% to 10%): Myalgia
Postmarketing reports: Rhabdomyolysis[Ref]

Nervous system

Very common (10% or more): Dysgeusia (including taste loss, taste perversion; up to 20%), headache (up to 17.1%)
Common (1% to 10%): Dizziness, paresthesia, somnolence, convulsion
Uncommon (0.1% to 1%): Intracranial hemorrhage
Postmarketing reports: Complex regional pain syndrome/reflex sympathetic dystrophy[Ref]

Ocular

Common (1% to 10%): Conjunctivitis (including lacrimation disorder)
Uncommon (0.1% to 1%): Eye hemorrhage[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 14%)
Common (1% to 10%): Depression, anxiety[Ref]

Some side effects of Torisel may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.