f the retinal pigment epithelium (RPE) and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and decreased foetal weights) occurred at a maternally toxic dosage.
Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential specific for these species, but are regarded as of no relevance for humans.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Norvir oral solution contains:
alcohol,
purified water,
polyoxyl 35 castor oil,
propylene glycol,
anhydrous citric acid,
saccharin sodium,
peppermint oil,
creamy caramel flavour,
sunset yellow E110.
6.2 Incompatibilities
Norvir should not be diluted with water.
6.3 Shelf lif
6 months
6.4 Special precautions for storage
Store below 25°C and use within the expiry date shown on the bottle. Do not refrigerate or freeze.
Avoid exposure to excessive heat. Keep the bottle tightly closed.
6.5 Nature and contents of container
Norvir oral solution is supplied in amber coloured multiple-dose polyethylene terephthalate (PET) bottles in a 90 ml size.
Two pack sizes are available for Norvir oral solution:
• 1 bottle of 90 ml (90 ml) plus one 7.5 ml dosing syringe.
• 5 bottles of 90 ml (450 ml) plus five 7.5 ml dosing syringes.
The 7.5 ml dosing syringe has graduations from 0.8 ml to 7.5 ml.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Shake well before each use. If, after shaking, particles or precipitate can be seen in the solution, the patient should take the next dose and see their doctor about a fresh supply.
The dosage cup or oral syringe should be cleaned immediately with hot water and dish soap after use. When cleaned immediately, drug residue is removed. The device must be dry prior to use
7. MARKETING AUTHORISATION HOLDER
Abbott Laboratories Limited
Abbott House,
Vanwall Business Park,
Vanwall Road,
Maidenhead,
Berkshire,
SL6 4XE
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/96/016/001
EU/1/96/016/008
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first a |
