Mycophenolate Mofetil

Registered South African indications:

• Prophylaxis of organ rejection

Contraindications 

• Hypersensitivity to mycophenolate mofetil, mycophenolic acid, or any of the excipients of mycophenolate mofetil
• Patients who are allergic to polysorbates (Tween)
• Pregnancy
• Breastfeeding
• Women of childbearing potential not using highly effective methods of contraception
• Mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor and should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome
• Mycophenolate mofetil oral suspension contains aspartame, a source of phenylalanine, and should not be given to patients with phenylketonuria

Cautions

• Severe renal impairment 
• Severe hepatic impairment (cardiac transplant patients)
• Elderly
• Porphyria
• High immunological risk
• Exposure to sunlight and ultraviolet light
• Persistent pulmonary symptoms, such as cough and dyspnoea
• Use of live attenuated vaccines
• Active serious digestive system disease
• Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (such as Lesch-Nyhan and Kelley-Seegmiller syndrome)
• Carriers of hepatitis B or hepatitis C
• Switching combination therapy from regimens containing immunosuppressants
• Phenylketonuria (sus)
• Fructose intolerance (sus)
• Ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap, inj, sus, tab

Prophylaxis of renal rejection

• Oral (cap, sus, tab): 1g, 12hrly
• IV: 1g, 12hrly

Prophylaxis of cardiac rejection
Treatment of first or refractory renal rejection

• Oral (cap, sus, tab): 1.5g, 12hrly
• IV: 1.5g, 12hrly

Prophylaxis of hepatic rejection

• Oral (cap, sus, tab): 1.5g, 12hrly
• IV: 1g, 12hrly

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Following reconstitution, the IV infusion must be administered slowly over a period of 2 hours by either a peripheral or a central vein

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If required, the powder for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter)

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See additional prescribing points 

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

Prophylaxis of renal rejection

Younger than 2 years 

• Not established for use

Between 2-18 years

• Oral (sus): 600mg/m², 12hrly; Max: 2g/24hrs 
• Oral (cap): Body surface area (BSA) 1.25-1.5m²: 750mg, 12hrly; Max: 1.5g/24hrs 
• Oral (cap, tab): BSA > 1.5m²: 1g, 12hrly; Max: 2g/24hrs 

Older than 18 years

• See adult dosage

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If required, the powder for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter)

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See additional prescribing points

Pregnancy 

• Contraindicated; positive evidence of risk
• Mycophenolate mofetil is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy
• Female patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations at the beginning of the treatment and must be counselled regarding pregnancy prevention and planning
• Before starting mycophenolate treatment, women of childbearing potential should have two negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL in order to exclude unintended exposure of the embryo to mycophenolate. It is recommended that the second test should be performed 8 – 10 days after the first test. For transplants from deceased donors, if it is not possible to perform two tests 8-10 days apart before treatment starts (because of the timing of transplant organ availability), a pregnancy test must be performed immediately before starting treatment and a further test performed 8-10 days later. Pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur
• Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy
• Spontaneous abortions have been reported in 45 to 49% of pregnant women exposed to mycophenolate mofetil, compared to a reported rate of between 12 and 33% in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil
• Based on literature reports, malformations occurred in 23 to 27% of live births in women exposed to mycophenolate mofetil during pregnancy (compared to 2 to 3 % of live births in the overall population and approximately 4 to 5% of live births in solid organ transplant recipients treated with immunosuppressants other than mycophenolate mofetil)
• Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to mycophenolate during pregnancy in combination with other immunosuppressants. The following malformations were most frequently reported:
  Abnormalities of the ear (e.g. abnormally formed or absent external ear), external auditory canal atresia (middle ear);
  Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits;
  Abnormalities of the eye (e.g. coloboma);
  Congenital heart disease such as atrial and ventricular septal defects;
  Malformations of the fingers (e.g. polydactyly, syndactyly);
  Tracheo-oesophageal malformations (e.g. oesophageal atresia);
  Nervous system malformations such as spina bifida;
  Renal abnormalities
• In addition, there have been isolated reports of the following malformations:
  Microphthalmia;
  Congenital choroid plexus cyst;
  Septum pellucidum agenesis;
  Olfactory nerve agenesis
• Studies in animals have shown reproductive toxicity
• Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to mycophenolate mofetil

Breastfeeding 

• Contraindicated
• Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breastfed infants, mycophenolate mofetil is contraindicated in breastfeeding mothers

Fertility

• MPA is a powerful teratogen
• It is not known if MPA is present in semen
• Calculations based on animal data show that the maximum amount of MPA that could potentially be transferred to a woman is so low that it would be unlikely to have an effect
• Mycophenolate has been shown to be genotoxic in animal studies at concentrations exceeding the human therapeutic exposures only by small margins such that the risk of genotoxic effects on sperm cells cannot completely be excluded
• Therefore, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 90 days after cessation of mycophenolate mofetil
• Male patients of reproductive potential should be made aware of and discuss with a qualified healthcare professional the potential risks of fathering a child

Renal Impairment 

Renal transplant patients:

• CrCl >25ml/min: No dose adjustment recommended
• CrCl <25ml/min: Caution; dose adjustment recommended
  Dosages that exceed 1g 12hrly should be avoided
  No adjustment is necessary for renal transplant patients experiencing delayed graft function postoperatively

Cardiac or hepatic transplant patients:

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

Hepatic Impairment

• Renal transplant patients: No dose adjustment recommended
  No adjustment necessary in severe hepatic parenchymal disease
• Cardiac transplant patients: Mild to moderate: No dose adjustment recommended
• Cardiac transplant patients: Severe: Caution; no information available

Elderly 

• Caution; no dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders 

• Agitation
• Confusion
• Depression
• Anxiety
• Abnormal thinking  
• Insomnia
• Seizures
• Tremor
• Somnolence
• Dizziness
• Headache
• Paraesthesia
• Dysgeusia
• Asthenia

Cardiovascular Disorders 

• Tachycardia
• Hypotension
• Hypertension
• Vasodilation
• Venous thrombosis

Respiratory Disorders 

• Pleural effusion
• Dyspnoea
• Cough
• Bronchiectasis
• Interstitial lung disease
• Pulmonary fibrosis

Gastrointestinal Disorders

• Nausea and vomiting  
• Abdominal pain
• Diarrhoea
• Gastrointestinal haemorrhage
• Ileus
• Colitis
• Gastrointestinal ulcer
• Gastritis
• Oesophagitis
• Stomatitis
• Constipation
• Dyspepsia
• Flatulence
• Eructation
• Abdominal distention
• Oesephagitis
• Gingival hyperplasia
• Mouth ulceration
• Pancreatitis
• Stomatitis
• Decreased appetite

Hepatobiliary Disorders 

• Hepatitis
• Jaundice
• Hyperbilirubinaemia
• Increased serum hepatic enzymes
• Increased alkaline phosphatase
• Blood lactate dehydrogenase increased

Genitourinary Disorders

• Renal impairment
• Haematuria
• Increased blood urea levels
• Increased serum creatinine

Endocrine and Metabolic Disorders

• Acidosis
• Hyperkalaemia
• Hypokalaemia
• Hyperglycaemia
• Hypomagnesaemia
• Hypocalcaemia
• Hypercholesterolaemia
• Hyperlipidaemia
• Hypophosphataemia
• Hyperuricaemia
• Gout
• Weight loss

Musculoskeletal Disorders

• Arthralgia
• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Rash
• Acne
• Alopecia
• Skin hypertrophy
• Benign neoplasm of skin
• Skin cancer

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Sepsis
• Infections and infestations (bacterial, fungal, protozoal, viral)
• Leucopenia
• Thrombocytopenia
• Anaemia
• Pancytopenia
• Leukocytosis
• Protozoal infections
• Lymphoma
• Agranulocytosis
• Neutropaenia
• Lymphoproliferative disorder
• Lymphocele
• Pure red cell aplasia
• Bone marrow failure
• Pseudolymphoma
• Ecchymosis
• Hypogammaglobulinaemia
• Pyrexia
• Chills

Others

• Neoplasm
• Oedema
• Hernia
• Pain

• Aciclovir
• Antacids  
• Proton pump inhibitors  
• Agents that interfere with enterohepatic circulation
• Cholestyramine
• Ciclosporin A
• Aminoglycosides
• Cephalosporins
• Fluoroquinolones
• Penicillins
• Ciprofloxacin
• Amoxicillin/clavulanic acid
• Norfloxacin
• Metronidazole
• Agents that affect glucuronidation
• Telmisartan
• Isavuconazole
• Ganciclovir
• Rifampicin
• Sevelamer
• Tacrolimus
• Probenecid
• Agents that undergo renal tubular secretion
• Live vaccines
• Azathiopine

• Full blood count

Specific cases may require

• Renal function
• Hepatic function
• Serum immunoglobins

Administration guidelines

• Oral suspension: Tap the bottle to loosen the powder. Measure 94ml purified water in a graduated cylinder and pour half into the bottle. Shake the bottle well for 1 minute, add the remainder of the water and shake for another minute. Shelf life: 60 days if stored below 30 ^oC
• IV infusion: Reconstitute to a concentration of 6mg/ml in the following steps: Reconstitute the contents of each vial by injecting 14ml 5% dextrose, gently shake the vial to dissolve the medication. To prepare 1g of MMF, dilute the content of 2 vials into 140ml of 5% dextrose for a volume of 168ml. To prepare 1.5g of MMF, dilute the content of 3 vials into 210ml of 5% dextrose for a volume of 252ml. Infusion rate: 84ml/hr
• Discard the infusion solution if particulate matter or discolouration is observed
• If the infusion solution is not prepared immediately prior to administration, the administration of the solution should be within 3 hours from reconstitution and dilution of the medicinal product. Keep solutions at 15 – 30°C

Safety of handling

• Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, direct contact with dry powder contained in formulations with skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water

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Tablet 500mg, Capsule 250mg - EML (Tertiary)

Suspension 200mg/ml, Injection 500mg - Non-EML 

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA) which is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase. It therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

Capsule 250mg

• Cimune (Abex)
• Cellcept (Roche)
• Mycocept (Sandoz) 
• Mycophenolate (Teva)
• Mycokem (Alkem)
• Mymune 250 (Sandoz)

Tablet 500mg

• Cimune (Abex)
• Cellcept (Roche) originator
• Immunolate (Zydus)
• Micomune fct (Ingwe)
• Mycocept (Sandoz) 
• Mycophenolate (Teva)
• Mycokem (Alkem)

Suspension (per ml) 200mg

• Cellcept os (Roche) originator

Injection (per vial) 500mg

• Cellcept (Roche) originator