Tacrolimus

Registered South African indications:

• Prophylaxis and treatment of transplant rejection: Liver, kidney & heart 

Prolonged-release formulations of tacrolimus are not inter-changeable with immediate-release formulations of tacrolimus without careful monitoring and supervision by a transplant specialist.

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to macrolides
• Known hypersensitivity to polyoxyethylated castor oil (HCO-60) or structurally related compounds (PR cap, inj)
• Pregnancy
• Lactation
• As tacrolimus may alter the metabolism of oral contraceptives, other forms of contraception should be used
• Concomitant administration of live attenuated vaccines
• Concomitant administration with ciclosporin
• Concomitant use with grapefruit juice

Cautions

• Renal impairment
• Severe hepatic impairment
• Elderly
• Diarrhoea
• History of or risk factors for QT prolongation
• Exposure to sunlight and ultraviolet light
• History of or risk factors for parvovirus B19 infection
• Galactose intolerance (cap)
• Lapp lactase deficiency (cap)
• Glucose-galactose malabsorption (cap)

Forms avail. in SA and covered in this monograph: Prolonged release capsule (PR cap), cap, inj

Kidney transplant - prophylaxis

• Oral (PR cap): 0.2-0.3mg/kg, dly; Should be administered within 24hrs of completion of surgery
• Oral (cap): 0.15-0.4mg/kg/day, in 2 divided doses; Should be administered within 24hrs of completion of surgery
• IV infusion: 0.05-0.1mg/kg/day, as a continuous infusion for 24hrs; Should be administered within 24hrs of completion of surgery

Liver transplant - prophylaxis

• Oral (PR cap): 0.1-0.2mg/kg, dly; Should be started within 12-18hrs of completion of surgery
• Oral (cap): 0.1-0.2mg/kg/day, in 2 divided doses; Should be started within 12hrs of completion of surgery
• IV infusion: 0.01-0.05mg/kg/day, as continuous infusion for 24hrs; Should be started within 6hrs of completion of surgery

Heart transplant - prophylaxis

• Oral (cap): 0.075mg/kg/day, in 2 divided doses
• IV infusion: 0.01-0.02mg/kg/day

Heart transplant - treatment

• Oral (PR cap): 0.15mg/kg, dly
• Oral (cap): 0.15mg/kg/day, in 2 divided doses

IV infusion: 0.05mg/kg/day, as continuous infusion

---

Prolonged release formulations are not interchangeable with immediate-release formulations. Consultation with a transplant specialist is required.

Paed. forms avail. in SA and covered in this monograph: cap, inj

Kidney transplant - prophylaxis

• Oral (cap): 0.3mg/kg/day, in 2 divided doses
• IV infusion: 0.075-0.1mg/kg/day, as a 24hr infusion

Liver transplant - prophylaxis

• Oral (cap): 0.3mg/kg/day, in 2 divided doses
• IV infusion: 0.05mg/kg/day, as a 24hr infusion

Heart transplant - prophylaxis

• Oral (cap): 0.1-0.3mg/kg/day, in 2 divided doses
• IV infusion: 0.03-0.05mg/kg/day, as a 24hr infusion

Heart transplant - treatment

• Oral (cap): 0.2-0.3mg/kg/day, in 2 divided doses

Pregnancy

• Contraindicated

Breastfeeding

• Contraindicated

Renal Impairment

• Caution; no dose adjustment recommended
  Careful monitoring of renal function is recommended to guide subsequent dosing

Hepatic Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  Lower starting doses may be required

Elderly

• Caution; no dose adjustment recommended 
  Start at lower end of dosing range

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Tremor
• Headache
• Seizures
• Disturbances in consciousness
• Paraesthesias 
• Dysaesthesias
• Peripheral neuropathy 
• Dizziness
• Coma
• Central nervous system haemorrhages
• Cerebrovascular accidents
• Paralysis
• Paresis
• Encephalopathy
• Speech and language abnormalities 
• Amnesia
• Hypertonia
• Myasthenia
• Insomnia
• Anxiety
• Confusion
• Disorientation
• Depression
• Nightmare 
• Hallucination
• Psychotic disorder

Cardiovascular Disorders

• Ischaemic coronary artery disorders 
• Tachycardia
• Ventricular arrhythmias 
• Cardiac arrest 
• Heart failures
• Cardiomyopathies
• Ventricular hypertrophy
• Supraventricular arrhythmias 
• Palpitations
• Pericardial effusion
• Torsades de pointes
• Hypertension
• Haemorrhage
• Thrombembolic and ischaemic events 
• Peripheral vascular disorders  
• Hypotensive disorders
• Infarction 
• Deep venous thrombosis 
• Shock

Respiratory Disorders

• Dyspnoea
• Parenchymal lung disorders 
• Pleural effusion
• Pharyngitis
• Cough
• Nasal congestion and inflammation
• Respiratory failure
• Respiratory tract disorders 
• Asthma
• Acute respiratory distress syndrome

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Gastrointestinal inflammatory conditions
• Gastrointestinal ulceration and perforation 
• Gastrointestinal haemorrhage 
• Stomatitis
• Ulceration 
• Ascites
• Gastrointestinal and abdominal pains 
• Constipation 
• Flatulence
• Bloating 
• Distension 
• Loose stools
• Paralytic ileus 
• Acute and chronic pancreatitis
• Gastrooesophageal reflux disease 
• Impaired gastric emptying
• Sub ileus 
• Pancreatic pseudocyst

Hepatobiliary Disorders

• Cholestasis
• Jaundice
• Hepatocellular damage 
• Hepatitis
• Cholangitis
• Hepatitic artery thrombosis 
• Venoocclusive liver disease
• Hepatic failure 
• Bile duct stenosis

Genitourinary Disorders

• Renal impairment
• Renal failure
• Oliguria
• Renal tubular necrosis 
• Nephropathy
• Anuria
• Haemolytic uraemic syndrome
• Nephropathy 
• Haemorrhagic cystitis
• Dysmenorrhoea
• Uterine bleeding

Endocrine and Metabolic Disorders

• Hirsutism
• Hyperglycaemic conditions 
• Diabetes mellitus
• Hyperkalaemia
• Hypomagnesaemia
• Hypophosphataemia 
• Hypokalaemia
• Hypocalcaemia 
• Hyponatraemia 
• Fluid overload
• Hyperuricaemia
• Decreased appetite
• Metabolic acidosis 
• Hyperlipidaemia
• Hypercholesterolaemia 
• Hypertriglyceridaemia 
• Dehydration
• Hypoproteinaemia
• Hyperphosphataemia 
• Hypoglycaemia

Musculoskeletal Disorders

• Arthralgia
• Muscle spasms 
• Pain in limb 
• Back pain
• Joint disorders
• Decreased mobility

Skin and Subcutaneous Tissue Disorders

• Pruritus 
• Rash
• Alopecia
• Acne
• Increased sweating
• Dermatitis 
• Photosensitivity
• Toxic epidermal necrolysis 
• Stevens-Johnson syndrome

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Leukopenia
• Thrombocytopenia 
• Leukocytosis
• Coagulopathies
• Abnormal coagulation and bleeding analyses 
• Pancytopenia
• Neutropenia
• Thrombotic thrombocytopenic purpura
• Hypoprothrombinaemia 
• Pure red cell aplasia 
• Agranulocytosis 
• Haemolytic anaemia
• Allergic and anaphylactoid reactions

Sensory Disorders

• Blurred vision 
• Photophobia 
• Eye disorders
• Cataract
• Blindness
• Tinnitus
• Hypoacusis
• Deafness 
• Impaired hearing

• CYP3A4 inhibitors
• CYP3A4 inducers
• Live attenuated vaccines
• Ciclosporin
• Neurotoxic agents
• Nephrotoxic agents
• Agents that increase serum potassium
• Lansoprazole
• Fusidic acid
• Non-steroidal anti-inflammatory drugs
• Oral anticoagulants
• Oral antidiabetics
• Magnesium
• Aluminium
• Metoclopramide
• Cimetidine
• Prednisone
• Methylprednisolone
• Metamizole
• Carbamazepine
• Isoniazid
• Phenytoin
• Statins
• Contraceptives
• Phenazone
• Phenobarbital

Other interactions

• Grapefruit juice

• Serum drug levels
• Blood pressure
• ECG
• Fasting blood glucose
• Electrolytes
• Hepatic function
• Renal function
• Full blood count 
• Coagulation values
• Plasma protein levels

Tacrolimus binds to a cytosolic protein which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes. Tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines and the expression of the interleukin-2 receptor.

Capsule 0.5mg

• Prograf (Astellas) originator
• Tacrum (Cipla Medpro)
• Tarograf  (Accord)
• Talomune 0,5 mg (Strides Pharma)

Capsule 1mg

• Prograf (Astellas) originator
• Tacrum (Cipla Medpro)
• Tarograf (Accord)
• Talomune 1 mg (Strides Pharma)

Capsule 5mg

• Prograf (Astellas) originator
• Tacrum (Cipla Medpro)
• Tarograf (Accord)
• Talomune 5 mg (Strides Pharma)

Prolonged-release capsule 0.5mg

• Advagraf (Astellas) originator

Prolonged-release capsule 1mg

• Advagraf (Astellas) originator

Prolonged-release capsule 5mg

• Advagraf (Astellas) originator

Injection (per ml) 5mg

• Prograf (Astellas) originator