October 1999
October 1999
FORMULARY ADDITIONS
Rosiglitazone (Avandiaâ )
2 mg, 4 mg, and 8 mg Tablets
Thiazolidinedione antidiabetic agents like rosiglitazone, represent a different chemical class in the treatment of diabetes, and have a different pharmacological action than other products currently available. All agents in this class improve insulin sensitivity in the muscle and adipose tissue, inhibit hepatic gluconeogenesis, reduce circulating levels of free fatty acids, and reduce hyperinsulinemia and hyperlipidemia. Rosiglitazone is indicated for use in Type 2 diabetes as monotherapy and in combination with metformin in patients inadequately controlled with diet and exercise. Rosiglitazone is 60- to 200-fold more potent than troglitazone or pioglitazone.
The initial starting dose of rosiglitazone as monotherapy is 4-mg once daily or 2-mg twice daily. The dose can be increased in increments of 4-mg per day after 12 weeks, to a maximum daily dose of 8-mg. When used in combination with metformin, the dosing guidelines are the same as with monotherapy.
Rosiglitazone should not be used to treat patients with Type 1 diabetes or diabetic ketoacidosis since it is active only in the presence of insulin. Some patients may experience a decrease in hemoglobin and hematocrit during the first 4 to 12 weeks of therapy. Edema may also develop in some patients. Rosiglitazone should be used with caution in patients with heart failure and avoided in patients with NYHA Class 3 and 4 unless the expected benefit is judged to outweigh the potential risk. The development of liver dysfunction is a concern in this class of antidiabetic agents. In July 1998, changes in troglitazone’s product labeling regarding more stringent liver function monitoring intended to reduce risk of severe liver injury. The labeling of rosiglitazone indicates that patients treated in the clinical trials displayed no evidence of drug-induced hepatotoxicity or elevations of ALT levels. However, in double blinded trials in the US, approximately six patients have developed increased ALT levels with rosiglitazone. Therefore, liver function tests are recommended at the start of therapy and then every 2 months during the first year and periodically thereafter. If the ALT should rise, it should be monitored closely; if it exceeds three times the upper limit of normal, the drug should be discontinued. If the patient had previously experienced jaundice while taking troglitazone, they should not be treated with rosiglitazone. When switching a patient with normal hepatic function from troglitazone to rosiglitazone, troglitazone should be discontinued at least 1 week before the start of the newer agent.
In premenopausal anovulatory patients with insulin resistance, treatment with this class of agents may result in the resumption of ovulation.
Adverse reactions for rosiglitazone include upper respiratory tract infection, headache, back pain, hyperglycemia, fatigue, sinusitis, diarrhea and hypoglycemia. The incidence of hypoglycemia was higher when rosiglitazone was used in combination therapy with metformin or sulfonylureas as compared to monotherapy (1.3% vs 5.9% vs 0.6%, respectively).
Rosiglitazone has an FDA pregnancy category rating of C and should not be administered to a breast-feeding woman.
FOOD/DRUG INTERACTIONS: Rosiglitazone can be taken without regard to food. Drug interactions are listed in Table 1.
Table 1. Summary of drug interactions with Rosiglitazone
Interacting Drug |
Rosiglitazone (RSG) |
Acarbose |
Reduction in RSG AUC (12%) and T1/2 (1 hr): Not clinically significant |
Alcohol |
Did not increase risk of acute hypoglycemia |
Digoxin |
No effect |
Glyburide |
No effect |
Metformin |
No effect |
Nifedipine |
Mild reduction in nifedipine AUC: Not clinically significant |
Oral Contraceptives |
No effect |
Warfarin |
No effect |
CYP3A4 |
Does not appear to inhibit or induce CYP3A4 metabolism |
Infliximab (Remicadeâ )
100mg/20mL vials
Many inflammatory mediators play a large part in Crohn’s disease, such as macrophages, monocytes and T-cells, which all produce a substance known as Tumor Necrosis Factor-Alpha (TNFa ). Infliximab, a monoclonal antibody to TNFa , neutralizes TNFa ’s biological activity by binding. This mechanism of action is unlike any other chemical moiety presently available. Infliximab is indicated for:
- treatment of moderately and severely active Crohn’s disease for the reduction of the signs and symptoms in patients who have an inadequate response to conventional therapy.
- treatment of patients with fistulizing Crohn’s disease for the reduction in the number of draining enterocutaneous fistula(s).
The recommended dose of Infliximab is 5 mg/kg given as a single intravenous infusion for treatment of moderately to severely active Crohn’s disease. In patients with fistulizing disease, an initial 5 mg/kg dose should be followed by additional 5 mg/kg doses at 2 and 6 weeks after the first infusion. Infliximab is Pregnancy Category C and it is not known whether it can cause fetal harm when administered to a pregnant woman or if it is excreted in human milk or absorbed systemically after ingestion.
At the present time, no studies compare Infliximab to other treatments available for Crohn’s disease. Efficacy has been studied only in placebo-controlled studies.
Infliximab should not be administered to patients with known hypersensitivity to any murine proteins or other components of the product. Warnings associated with Infliximab include hypersensitivity reactions and formation of autoimmune antibodies, possibly developing into a lupus-like syndrome. Precautions include immunosuppression, malignancy/infection (specifically lymphomas) and human antichimeric antibody (HACA) development, predisposing the patient more likely to experience an infusion reaction. In premarketing clinical trials, 5% of the patients receiving Infliximab discontinued scheduled infusions due to adverse experiences, most frequently infusion reactions and infections. Infliximab infusions can be accompanied by nonspecific symptoms, such as fever or chills, pruritus, urticaria, cardiopulmonary or a combination of these. Additionally, a large group of patients experienced infections, including suspected pneumonia, cellulitis and infection at a central venous catheter, sepsis, cholecystitis, endophalmitis and furunculosis. A small amount of infliximab patients testing positive for antinuclear antibodies (ANA) increased from 24% at screening to 36% at the last evaluation.
In November 1998, the manufacturer released new information regarding changes of adverse reactions seen with Infliximab. In a trial of 40 patients retreated with Infliximab two to four years after therapy, ten patients developed side effects 3 to 12 days following retreatment. The symptoms included myalgia (90%), rash (70%), fever (60%), polyarthralgia (50%) and other side effects to a smaller extent. In addition, antibodies to Infliximab were discovered and my have shortened the duration of clinical response. Nine of the 10 patients experiencing these effects were initially treated with an investigational liquid formulation of Infliximab, which has been replaced by a lyophilized formulation. It is unknown if the liquid formulation was a factor in causing these effects following retreatment.
Patients receiving immunosuppressants tended to experience fewer infusion reactions as compared to patients on no immunosuppressants. The manufacturer has not established specific monitoring for infliximab.
The Pharmacy and Therapeutics committee approved infliximab for the sole indication of patients with refractory Crohn’s disease. In regards to the cost and safety of infliximab, all indications other than the approved indication require a non-formulary request form to be submitted.
FOOD/DRUG INTERACTIONS: Infliximab may be taken without regard to food. Specific studies on drug interactions with infliximab have not been conducted.
FORMULARY DELETIONS
Troglitazone (Rezulinâ ): 200mg, 300mg and 400mg Tablets
Based on numerous reports of hepatic toxicity with troglitazone, the pharmacy and therapeutics committee has decided to delete troglitazone from the formulary.
