P&T News: January 1998

Safety Updates: Low Molecular Weight Heparin, Metformin, and Troglitazone

Unknown Author
Peer Review Status: Internally Peer Reviewed by Bradley Britigan, M.D., Kevin Bebout, R.Ph., Alan Mutnick, Pharm.D., and Mary Ross, M.B.A.

During recent weeks safety warnings have been issued for low molecular weight heparins, metformin, and troglitazone by the FDA and/or the respective manufacturers. This new safety information is summarized in this issue of the P& T News.\par

Low Molecular Weight Heparin
The FDA has issued a warning letter about post-marketing reports of patients who have developed epidural or spinal hematomas with the concurrent use of low molecular weight heparin (LMWH) and spinal/epidural anesthesia or spinal puncture. Many of the hematomas caused neurologic injury, including long-term or permanent paralysis. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. However, given the potential seriousness of this complication, it is believed that patients and health care professionals should be notified of this information.

The postmarketing reports received to date involved patients who were treated with enoxaparin (Lovenox[R]) injection. However, the adverse event would be expected to occur if drugs with similar pharmacological activity were used in the same manner. Therefore, the FDA asked all manufacturers of low molecular weight heparins and heparinoids [e.g., dalteparin (Fragmin[R] - Pharmacia & Upjohn), ardeparin (Normiflo[R] - Wyeth), danaparoid (Orgaran[R] - Organon[R]] to revise their package inserts to provide further information for safe and effective use of these drugs. Specifically, the manufacturers have been asked to include additional safety information and recommendations in a boxed warning in their package inserts.

Summary of Reports

At this time, the FDA believes practitioners should be aware of the following points if using these products:

Metformin
Since its marketing in the United States in May 1995, the FDA has received over 65 reports of lactic acidosis in patients treated with metformin (Glucophage[R] - Bristol-Myers Squibb). In 47 patients, the diagnosis was confirmed by laboratory finding (lactate values 2 5 mmol/L). Of the 47 patients with confirmed diagnoses, 43 had one or more risk factors for lactic acidosis. Thirty had preexisting cardiac disease (18 had histories of congestive heart failure). Thirteen patients had preexisting renal insufficiency (two undergoing dialysis). Three patients had chronic pulmonary disease with hypoxia. Eight patients were over the age of 80 years. Only four patients had no apparent risk factors when treatment with metformin was initiated, and all four recovered.

The risk of lactic acidosis, a rare (0.03 cases per 1000 patient-year exposure) but serious and potentially life- threatening condition (up to half the cases may be fatal), can be reduced by continuing to avoid the use of metformin in patients:

Although the incidence of lactic acidosis is rare and is consistent with the worldwide experience, a thorough review of all reported cases indicates that there is an opportunity to increase physicians' ability to more appropriately select patients and help minimize the risk of lactic acidosis. Therefore, the following revisions to the metformin package insert are being made. These revisions are intended to help physicians better define appropriate patients for metformin therapy.

Patients More Than or Equal to 80 Years of Age
Renal function is an important consideration in selecting appropriate patients for metformin. Because aging is generally associated with a decline in renal function, it is now recommended that a creatinine clearance rate assessment be obtained in patients more than or equal to 80 years of age prior to the initiation of metformin therapy. Metformin treatment should not be initiated in patients 2 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not impaired.

Patients with Congestive Heart Failure (CHF)
The existence of CHF in a patient with type 2 diabetes increases the risk for hypoperfusion, hypoxia, and possible renal insufficiency. This is particularly true in patients with severe heart failure. Since any of these conditions may increase the risk of lactic acidosis, it is prudent to contraindicate the use of metformin in all patients with CHF who require pharmacologic treatment.

Metformin should also be avoided in patients with impaired hepatic function, excessive alcohol intake (acute or chronic), or acute or chronic metabolic acidosis, including diabetic ketoacidosis. Temporarily withhold the drug in patients receiving parenteral iodinated contract materials. Metformin is not recommended for pediatric patients or pregnant women.

"Dear Doctor Letter" Bristol-Myers Squibb January 1998 N Engl J Med 1998; 338:265-6.

Troglitazone: Liver Function Monitoring
The manufacturer of troglitazone (Rezulin[R] - Parke-Davis) has issued revised prescribing information, including "black-boxed" warnings, to apprise prescribers of idiosyncratic hepatocellular injury in patients being treated with the drug. The reports ranged from mild elevations of serum transaminases to one liver transplant and one death. This information has resulted in a new recommendation that liver enzymes and bilirubin levels of troglitazone-treated patients be measured at the start of therapy and monthly for the first six months of therapy. These tests should then be measured every two months for the remainder of the first year of therapy, and periodically thereafter.

Additional adverse reactions have also been noted during the post-marketing period. Outlined below are the changes in the prescribing information.

WARNINGS
Hepatic
Rare cases of severe idiosyncratic hepatocellular injury have been reported during marketed use. The hepatic injury is usually reversible, but very rare cases of hepatic failure, leading to death or liver transplant, have been reported. Injury has occurred after both short- and long-term troglitazone treatment.

During all clinical studies in North America, a total of 48 of 2510 (1.9%) troglitazone-treated patients and 3 of 475 (0.6%) placebo-treated patients had ALT levels greater than 3 times the upper limit of normal. Twenty of the troglitazone-treated and one of the placebo-treated patients were withdrawn from treatment. Two of the 20 troglitazone-treated patients developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional troglitazone-treated patient had a liver biopsy which was also consistent with an idiosyncratic drug reaction.

It is recommended that serum transaminase levels be checked at the start of therapy, monthly for the first six months of therapy, every two months for the remainder of the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Troglitazone therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT > 3 times the upper limit of normal) and should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g., ALT > 3 times the upper limit of normal).

PRECAUTIONS
Information for Patients
Patients who develop nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine or other symptoms suggestive of hepatic dysfunction or jaundice should immediately report these signs or symptoms to their physician.
 
ADVERSE REACTIONS
Postintroduction Reports
Adverse events associated with troglitazone that have been reported since market introduction, and for which causal relationship to drug has not been established include the following: congestive heart failure, weight gain, edema, fever, abnormal lab tests including increased CPK and creatinine, hyperglycemia, syncope, anemia, malaise.

Health care professionals are encouraged to report any unexpected adverse events associated with the use of troglitazone, especially those suggestive of idiosyncratic hepatocellular injury.

Note: The prescribing of troglitazone at UIHC is restricted to Endocrinology.

"Dear Doctor Letter" Parke-Davis, October 31, 1997
"Dear Doctor Letter" Parke-Davis, December 1, 1997

PHARMACY AND THERAPEUTICS SUBCOMMITTEE ACTIONS

DRUGS ADDED TO STOCK

ACITRETIN Capsules: 10 mg, 25 mg Acitretin (Soriatane[R] - Roche) is a retinoid indicated for treatment of severe psoriasis. Note Due to its teratogenic potential, the prescribing of acitretin is restricted to Dermatology.

BUDESONIDE Oral Inhaler: 200 mcg per inhalation Budesonide oral inhaler (Pulmicort.[R] Turbuhaler - Astra) is a corticosteroid indicated for maintenance treatment of asthma in patients 6 years of age and older.

CONJUGATED ESTROGENS PLUS MEDROXYPROGESTERONE Tablets: 0.625 mg plus 2.5 mg This combination product (PremPro[R] - Wyeth-Ayerst) is indicated for the treatment of vasomotor symptoms associated with menopause, the treatment of vulvar and vaginal atrophy, and the prevention of osteoporosis.

FOMEPIZOLE Injection: 1 g per ml Fomepizole (Antizole[R] - Orphan Medical) is an alcohol dehydrogenase inhibitor indicated as an antidote for ethylene glycol poisoning.

LAMIVUDINE PLUS ZIDOVUDINE Tablets: 150 mg plus 300 mg This combination product (Combivir[R] - GlaxoWellcome) is indicated for the treatment of HIV infection.

SAQUINAVIR Capsule, Soft Gelatin: 200 mg Saquinavir is an inhibitor of HIV. The formulation in the soft gelatin capsule (Fortovase[R] - Roche) is better absorbed and has better bioavailability than the previous formulation (Invirase[R]).

TIAGABINE Tablets: 4 mg, 12 mg, 16 mg, 20 mg Tiagabine (Gabitril - Abbott) is an anticonvulsant indicated for adjunctive therapy of partial seizures.

TUBOCURARINE Injection: 3 mg per ml Tubocurarine is a nondepolarizing neuromuscular blocking agent.

ADDITIONAL ACTIONS

VALACYCLOVIR 1 g TABLETS The 1 g tablet has been added to stock.

LIDOCAINE 1% INJECTION A 5 ml vial of a preservative-free product has been

Title Page