Temsirolimus

Registered South African indications:

• Advanced renal cell carcinoma

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to temsirolimus' metabolites (including sirolimus)
• Hypersensitivity to polysorbate 80
• Moderate to severe hepatic impairment (mantle cell lymphoma patients)

Cautions

• Known hypersensitivity to H1 antihistamine or in patients that cannot receive the antihistamine for medical reasons
• Pregnancy
• Breastfeeding
• Males and females of reproductive potential
• Severe renal impairment
• Mild to moderate hepatic impairment (advanced renal cell carcinoma patients)
• Mild hepatic impairment (mantle cell lymphoma patients)
• Elderly
• Porphyria
• Patients with central nervous system tumours
• Baseline neutropenia 
• High doses
• Exposure to sunlight and ultraviolet light (in patients with increased risk for skin cancer)
• Diabetes mellitus
• Pre-existing hyperlipidaemia
• Peri-surgical period
• Patients requiring wound care therapy
• Alcoholism
• Epilepsy
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Advanced renal cell carcinoma
  - In patients who have at least three of six prognostic risk factors
• Relapsed and/or refractory mantle cell lymphoma 

Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Caution
• There is no adequate data from the use of temsirolimus in pregnant women
• Studies in animals have shown reproductive toxicity. In reproduction studies in animals, temsirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification) in rats and rabbits. Teratogenic effects (omphalocele) were seen in rabbits
• The potential risk for humans is unknown. Due to the unknown risk related to potential exposure during early pregnancy, women of childbearing potential must be advised not to become pregnant while using temsirolimus. Men with partners of childbearing potential should use medically acceptable contraception while receiving temsirolimus
• Temsirolimus must not be used during pregnancy, unless the risk for the embryo is justified by the expected benefit for the mother

Breastfeeding

• Caution; not recommended
• It is unknown whether temsirolimus is excreted in human breast milk
• The excretion of temsirolimus in milk has not been studied in animals. However, sirolimus, the main metabolite of temsirolimus, is excreted in milk of lactating rats
• Because of the potential for adverse reactions in breast-fed infants from temsirolimus, breastfeeding should be discontinued during therapy

Fertility

• In male rats, decreased fertility and partly reversible reductions in sperm counts were reported

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

Hepatic Impairment

- Advanced renal cell carcinoma

• Mild to moderate: Caution; no dose adjustment recommended
  Severe: Caution; dose adjustment recommended

- Mantle cell lymphoma

• Mild: Caution; no dose adjustment recommended
  Moderate to severe: Contraindicated

Elderly         

• Caution; no dose adjustment recommended
  Elderly are more likely to experience certain adverse reactions

Porphyria Information

• Possibly porphyrinogenic (PSP)
  Through inhibition of ALAS1-induction, temsirolimus might protect against attacks of acute porphyria. On the other hand, experience seems to suggest that infection may trigger attacks of acute porphyria. Common side effects such as nausea and vomiting may be potentially porphyrogenic through reduction in food intake, especially carbohydrates

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Depression
• Anxiety
• Headache
• Dizziness
• Paraesthesia
• Somnolence
• Ageusia
• Intracranial haemorrhage
• Asthenia
• Fatigue

Cardiovascular Disorders

• Pericardial effusion
• Hypertension
• Venous thromboembolism (including deep vein thrombosis)
• Thrombophlebitis
• Chest pain
• Oedema
  - Generalised oedema
  - Facial oedema
  - Peripheral oedema
  - Scrotal oedema
  - Genital oedema

Respiratory Disorders

• Dyspnoea
• Cough
• Epistaxis
• Interstitial lung disease
  - Pneumonitis
  - Alveolitis
  - Allergic alveolitis
  - Pulmonary fibrosis
  - Eosinophilic pneumonia
• Pleural effusion
• Pulmonary embolism

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Stomatitis
• Constipation
• Abdominal pain
• Gastrointestinal haemorrhage
  - Anal haemorrhage
  - Rectal haemorrhage
  - Haemorrhoidal haemorrhage
  - Lip and mouth haemorrhage
  - Gingival bleeding
• Gastritis
• Dysphagia
• Abdominal distension
• Aphthous stomatitis
• Gingivitis
• Oral pain
• Intestinal/duodenal perforation

Hepatobiliary Disorders

• Increased aspartate aminotransferase
• Increased alanine aminotransferase

Genitourinary Disorders

• Increased blood creatinine
• Renal failure

Endocrine and Metabolic Disorders

• Hyperlipidaemia
• Hyperglycaemia
• Hypercholesterolaemia
• Hypertriglyceridaemia
• Hypokalaemia
• Decreased appetite
• Diabetes mellitus
• Dehydration
• Hypocalcaemia
• Hypophosphataemia

Musculoskeletal Disorders

• Back pain
• Arthralgia
• Myalgia
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Rash
  - Pruritic rash
  - Maculopapular rash
  - Generalised rash
  - Macular rash
  - Papular rash
• Pruritus (including generalised pruritis)
• Nail disorder
• Dry skin
• Dermatitis
• Exfoliative rash
• Acne
• Ecchymosis
• Petechiae
• Fungal skin infections
• Mucosal inflammation
• Impaired wound healing
• Stevens-Johnson syndrome

Immune, Blood and Lymphatic System Disorders

• Bacterial and viral infections
  - Cellulitis
  - Herpes zoster
  - Oral herpes
  - Influenza
  - Herpes simplex
  - Ophthalmic herpes zoster
  - Herpes virus infection
  - Bronchitis
  - Abscess
  - Wound infection
  - Post-operative wound infections
• Pneumonia (including interstitial pneumonia)
• Sepsis (including septic shock)
• Candidiasis
  - Oral
  - Anal
• Fungal infections
• Urinary tract infection (including cystitis)
• Upper respiratory tract infection
• Pharyngitis
• Sinusitis
• Rhinitis
• Folliculitis
• Laryngitis
• Anaemia
• Thrombocytopenia
• Neutropenia
• Leukopenia
• Hypersensitivity reactions/drug hypersensitivity  
• Lymphopenia
• Fever
• Chills
• Pneumocystis jiroveci pneumonia
• Angioneurotic oedema-type reactions

Sensory Disorders

• Conjunctivitis (including lacrimal disorder)
• Eye haemorrhage
• Dysgeusia

• Sunitinib 
• Anticoagulants
• Angiotensin-converting enzyme inhibitors
• Ramipril
• Calcium channel blockers
• Amlodipine
• CYP3A4/5 inducers
• Rifampicin
• Carbamazepine
• Phenobarbital
• Phenytoin
• CYP3A4 inhibitors 
• Ketoconazole
• Nelfinavir
• Ritonavir
• Itraconazole
• Voriconazole
• Nefazodone
• Diltiazem
• Verapamil
• Clarithromycin
• Erythromycin
• Aprepitant
• CYP3A4/5 substrates
• Vaccines, including live vaccines
  - Measles
  - Mumps
  - Rubella
  - Oral polio
  - Bacillus Calmette-Guérin
  - Yellow fever
  - Varicella
  - TY2Ia typhoid vaccine
• P-glycoprotein substrates
• Digoxin
• Vincristine
• Colchicine
• Dabigatran
• Lenalidomide
• Paclitaxel
• Amphiphilic agents
• Statins
• Interferon-alpha
• Amiodarone
• St John's wort
• Grapefruit juice

• Full blood count with differential  and platelets
• Serum glucose
• Renal function
• Hepatic function
• Lipid profile
• Chest x-ray
• Lung computed tomography

Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-temsirolimus complex binds and inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity results in a G1 growth arrest in treated tumour cells resulting from selective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc, and ornithine decarboxylase. Temsirolimus exerts its effect by binding in a complex with FKBP-12 and mTOR. When mTOR is bound in this complex, its ability to phosphorylate, and thereby control the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the PI 3 kinase/AKT pathway) that control cell division, is blocked. In addition to regulating cell cycle proteins, mTOR can regulate translation of the hypoxia-inducible factors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt to hypoxic microenvironments and to produce the angiogenic factor vascular endothelial growth factor (VEGF). The antitumour effect of temsirolimus, therefore, may also in part stem from its ability to depress levels of HIF and VEGF in the tumour or tumour microenvironment, thereby impairing vessel development.

Injection (per ml) 25mg

• Torisel (Pfizer) originator (Discontinued: 07/09/2021)