ROVISTAT

ROVISTAT

 Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the 
  rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to 
  mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is 
  the liver, the target organ for cholesterol lowering. 
- Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, 
  enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of 
  VLDL, thereby reducing the total number of VLDL and LDL particles.
- Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours 
  after oral administration. The absolute bioavailability is approximately 20%. 
- Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabol- 
  ism studies using human hepatocytes indicate that rosuvastatin is a poor substrate 
  for cytochrome P450-based metabolism. The main metabolites identified are the 
  N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximat- 
  ely 50% less active than rosuvastatin whereas the lactone form is considered clini-
  cally inactive. Rosuvastatin accounts for greater than 90% of the circulating
  HMG-CoA reductase inhibitor activity. 
- Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces 
  (consisting of absorbed and non-absorbed active substance) and the remaining part
  is excreted in urine. The plasma elimination half-life is approximately 19 hours.

Each film coated tablet of ROVISTAT® 10 mg contains:
  Rosuvastatin                           10 mg   (as rosuvastatin calcium)

ROVISTAT® is contraindicated:
- In patients with hypersensitivity to rosuvastatin or to any of the excipients.
- In patients with active liver disease including unexplained, persistent elevations of 
  serum transaminases and any serum transaminase elevation exceeding 3 x the upper
  limit of normal (ULN).
- In patients with severe renal impairment (Cr CL < 30 mL/mini). 
- In patients with myopathy. 
- In patients receiving concomitant cyclosporin. 
- During pregnancy and lactation and in women of childbearing potential not using
  appropriate contraceptive measures.
- The 40 mg dose is contraindicated in patients with pre-disposing factors for myopathy/ 
  rhabdomyolysis. Such factors include: moderate renal impairment (creatinine clear- 
  ance <60 ml/min), hypothyroidism, personal or family history of hereditary muscular 
  disorders, previous history of muscular toxicity with another HMG-CoA reductase
  inhibitor or fibrate, alcohol abuse, situations where an increase in plasma levels may
  occur, Asian patients, or concomitant use of fibrates.

- Cyclosporin: During concomitant treatment with ROVISTAT® and cyclosporin, 
  rosuvasta-in AUC values were on average 7 times higher than those observed in healthy
  volun- teers. 
- Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation 
   of treatment or dosage up-titration of ROVISTAT® in patients treated concomitantly
   with vitamin K antagonists (e.g. warfarin) may result in an increase in International 
   Norma- lised Ratio (INR). Discontinuation or down-titration of rosuvastatin may result 
   in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
- Gemfibrozil and other lipid-lowering products: Concomitant use of ROVISTAT®
   and gemfibrozil resulted in a 2-fold increase in rosuvastatin C-max and AUC. Gemfibro
   zil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin 
   (nicotinic acid) increase the risk of myopathy when given concomitantly with 
   HMG-CoA reductase inhibitors, probably because they can produce myopathy when
   given alone. The 40  mg dose is contraindicated with concomitant use of a fibrate.
- Antacid: The simultaneous dosing of ROVISTAT® with an antacid suspension
   containing aluminum and magnesium hydroxide resulted in a decrease in rosuvastatin 
   plasma concentration of approximately 50%. This effect was mitigated when the antacid 
  was dosed 2 hours after ROVISTAT® .
- Erythromycin: Concomitant use of ROVISTAT® and erythromycin resulted in a 20% 
  decrease in AUC and a 30% decrease in C-max of rosuvastatin. This interaction may be
  caused by the increase in gut motility caused by erythromycin.
- Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of 
  ROVISTAT® and an oral contraceptive resulted in an increase in ethinyl-estradiol and 
  norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should 
   be considered when selecting oral contraceptive doses. 
- Other medicinal products: Based on data from specific interaction studies no 
   clinically relevant interactions with digoxin is expected.
- Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that 
  ROVISTAT® is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In 
  addition, ROVISTAT® is a poor substrate for these isoenzymes. No clinically relevant
  interactions have been observed between rosuvastatin and either fluconazole or 
  ketoconazole. Concomitant administration of itraconazole  and rosuvastatin resulted in
  a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically 
  significant. Therefore, drug interactions resulting from cytochrome P450-mediated 
  metabolism are not expected.
 

ROVISTAT® is contraindicated in pregnancy and lactation.

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions
   tends to be dose dependent. The adverse events seen with ROVISTAT® are generally 
   mild and transient. In controlled clinical trials, less than 4% of ROVISTAT®-treated 
   patients were withdrawn due to adverse events
- Common: headache, dizziness, constipation, nausea, abdominal pain, myalgia,
   asthenia. 
- Uncommon: pruritus, rash and urticaria. 
- Rare: hypersensitivity reactions including angioedema, myopathy and rhabdomyoly
  sis. 
- Renal effects: Proteinuria has been observed in patients treated with ROVISTAT®.
  In most cases, proteinuria decreases or disappears spontaneously on continued 
  therapy, and has not been shown to be predictive of acute or progressive renal disease.
- Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in 
  transaminases has been observed in a small number of patients taking rosuvastatin; the
  majority of cases were mild, asymptomatic and transient.

An assessment of renal function should be considered during routine follow-up of 
  patients treated with a dose of 40 mg. 
- ROVISTAT®, as with other HMG-CoA reductase inhibitors, should be prescribed
   with caution in patients with pre-disposing factors for myopathy / rhabdomyolysis. In 
   such patients the risk of treatment should be considered in relation to possible benefit
   and clinical monitoring is recommended. If Creatine Kinase (CK) levels are 
   significantly elevated at baseline (>5xULN) treatment should not be started.
- Whilst on treatment, patients should be asked to report inexplicable muscle pain, 
   weakness or cramps immediately, particularly if associated with malaise or fever.   
   Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if 
   muscular symptoms are severe and cause daily discomfort (even if CK levels  are
    ≤5xULN).   If   symptoms   resolve   and  CK  levels  return to normal, then consideration
   should be given to reintroducing ROVISTAT® or an alternative HMG-CoA reductase
   inhi- bitor at the lowest dose with close monitoring. Routine monitoring of CK levels 
   in asymptomatic patients is not warranted. 
- ROVISTAT® should not be used in any patient with an acute, serious condition
   suggestive of myopathy or predisposing to the development of renal failure secondary
   to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, 
  endocrine and electrolyte disorders; or uncontrolled seizures).
- As with other HMG-CoA reductase inhibitors, ROVISTAT® should be used with 
   caution in patients who consume excessive quantities of alcohol and/or have a history 
   of liver disease. It is recommended that liver function tests be carried out prior to, and
   3 months following, the initiation of treatment. ROVISTAT® should be discontinued 
   or the dose reduced if the level of serum transaminases is greater than 3 times the upper
   limit of normal. In patients with secondary hypercholesterolaemia caused by 
  hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to
  initiating therapy with ROVISTAT®.
- Pharmacokinetic studies show an increase in exposure in Asian subjects compared with 
  Caucasians.

Effects on ability to drive and use machines:-
- When driving vehicles or operating machines, it should be taken into account that 
   dizziness may occur during treatment.

- Blister of 10 tablets, pack of 2 blisters. 

- Store below 25ºC, and protect from light.