NOVEMBER        2001

 

FORMULARY ADDITIONS

 

Insulin Glargine [rDNA origin] Injection (Lantus^®)

100 units/mL, 10 mL vials

 

 

Insulin glargine is a recombinant human insulin analog produced by a non-pathogenic laboratory strain of Escherichia coli.  It is indicated in both adult and pediatric patients with type 1 or type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. In its acidic formulation, LANTUS is completely soluble.  Upon injection into subcutaneous tissue, the acidic solution is neutralized and micro-precipitates form which slowly release small amounts of insulin glargine into the circulation, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing and substitutes as a patient’s basal insulin.

 

Table 1:  Insulin analogs used to manage type 1 and type 2 diabetes

 

LANTUS is contraindicated in patients hypersensitive to insulin glargine or its excipients. The prolonged duration of action of insulin glargine is dependent on its injection into subcutaneous tissue. For this reason, LANTUS should not be given intravenously. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia.

Hypoglycemia is the most common adverse effect of insulin, including LANTUS. Any change of insulin should be made cautiously and only under medical supervision. The prolonged effect of subcutaneous LANTUS may delay recovery from hypoglycemia.  In comparative clinical trials, subjects taking LANTUS had a 9-15 point lower incidence of nocturnal hypoglycemia than those taking NPH insulin. In addition, the number of subjects who experienced severe hypoglycemia was approximately 2-4 points lower in the LANTUS group than in the NPH group.

Lipodystrophy may occur at the injection site and delay insulin absorption.  Other injection site reactions include redness, pain, itching, hives, swelling, and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Most minor reactions to insulin usually resolve in a few days to a few weeks. Reports of mild injection site pain were approximately 12 times higher with LANTUS than human NPH insulin in comparative studies. This reaction is attributed to the more acidic pH of the LANTUS solution. No subjects discontinued treatment due to injection site reactions in these studies.  Other treatment-emergent injection site reactions other than pain at injection site occurred at similar incidences with both glargine and NPH insulin. Immediate-type allergic reactions are rare. Such reactions to insulin or its excipients may be associated with generalized skin reactions, angioedema, bronchospasm, hypotension, or shock and may be life threatening.

            Retinopathy was evaluated in the clinical studies by means of retinal adverse events reported and fundus photography. The numbers of retinal adverse events reported for LANTUS and NPH treatment groups were similar for patients with type 1 and type 2 diabetes. Progression of retinopathy was investigated by fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Study (ETDRS). In one clinical study involving patients with type 2 diabetes, a difference in the number of subjects with >3-step progression in ETDRS scale over a 6-month period was noted by fundus photography (7.5% in LANTUS group versus 2.7% in NPH treated group). The overall relevance of this isolated finding cannot be determined due to the small number of patients involved, the short follow-up period, and the fact that this finding was not observed in other clinical studies.

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.  A list of these medications is provided in table 2.

 

Table 2: Effects of drugs on glucose metabolism

Prepared 9/18/01.  This may not be a complete list.  For more information, contact the KU Drug Information Center at extension 8-2328.

 

LANTUS is administered as a daily subcutaneous bedtime injection. Clinical studies have shown there is no relevant difference in insulin glargine absorption after abdominal, deltoid, or thigh administration.  LANTUS is equipotent to intermediate- and long-acting insulins, allowing both human NPH and ultralente insulin to be converted to LANTUS on a unit-to-unit basis.  See table 3 for guidelines on initial dosing and for regimens to follow when switching from human NPH insulin to LANTUS.  When changing from an intermediate- or long-acting insulin to LANTUS, the amount and timing of short-acting insulin or the dose of oral antidiabetics may need to be adjusted. A program of close monitoring under medical supervision is recommended after switching insulins and for the initial weeks thereafter.

LANTUS can be safely administrated to pediatric patients greater than six years of age. Administration to those less than six years old has not been studied. Based on the results of a study in pediatrics, the recommendation for changeover to LANTUS from NPH is the same as described for adults.

 

Table 3: Initial Dosing Guidelines

 

LANTUS must not be diluted or mixed with any other insulin or solution. If LANTUS is diluted or mixed, the solution may become cloudy, and the pharmacokinetic/pharmacodynamic profile (e.g. onset of action, time to peak effect) may be altered in an unpredictable manner.  LANTUS is not the insulin of choice for the treatment of diabetic ketoacidosis. Intravenous short-acting insulin is the preferred treatment. Insulin glargine is available as a clear aqueous solution. Each mL of the injection contains 100 IU of insulin glargine and 30 mcg of zinc. Unopened LANTUS vials should be stored in the refrigerator.  Once opened, the 10 mL vial is good for 28 days.  Opened vials should be kept as cool as possible (stored under 86°F) and out of direct light and heat.

 

 

 

 

Valganciclovir (Valcyteä)

450 mg Tablets

 

 

            Valganciclovir, the L-valyl ester prodrug of ganciclovir, is recommended for use in the induction and maintenance treatment of cytomegalovirus (CMV) retinitis in adult patients with AIDS.  Ganciclovir triphosphate exhibits virustatic activity through inhibition of viral DNA synthesis.

            For induction therapy of active CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) twice daily with food for 21 days.  After induction treatment, or in patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) once daily with food. Valganciclovir dosage adjustments are recommended in patients with impaired renal function, specifically those with CrCl <60 ml/min.  The bioavailability of valganciclovir tablets is significantly higher than ganciclovir (Cytovene^Ò) capsules and cannot be substituted for ganciclovir capsules on a one-to-one basis.

            Valganciclovir is rapidly and completely hydrolyzed by hepatic and intestinal esterases to ganciclovir following oral administration. The absolute bioavailability of ganciclovir from valganciclovir is approximately 60%.  In contrast, the bioavailability of oral ganciclovir is approximately 6%.  In patients with renal impairment, ganciclovir clearance is reduced and the peak concentration, half-life, and AUC are increased. 

            Drug interaction studies were not conducted with valganciclovir, but drug interactions associated with ganciclovir should be expected to also occur with valganciclovir.  Patients on concomitant zidovudine therapy may be at increased risk for neutropenia and/or anemia because both agents can cause these adverse reactions when given alone.  Probenecid decreases the clearance of ganciclovir; therefore patients should be monitored closely for toxicity.  Patients with impaired renal function and on concomitant mycophenolate therapy should be monitored closely as levels of both metabolites may increase.

            The major toxicities of ganciclovir are blood dyscrasias, including neutropenia, anemia, and thrombocytopenia.  The most frequently observed adverse events during valganciclovir induction therapy include diarrhea, nausea, vomiting, fever, fatigue, headache, and oral candidiasis. Complete blood counts should be monitored every two days during induction and weekly during maintenance therapy.  Renal function should be monitored every two weeks due to observations of increased serum creatinine.

            Caution should be exercised in the handling of valganciclovir tablets.  Tablets should not be broken or crushed.  Valganciclovir is considered a potential teratogen and carcinogen in humans.  Caution should be used when handling broken tablets; direct contact with skin or mucous membranes should be avoided.  If contact occurs, wash thoroughly with soap and water and rinse eyes thoroughly with plain water.  Valganciclovir should be disposed of according to the guidelines for disposal of antineoplastic agents.

 

 

 

 

 

 

Lopinavir/ritonavir (Kaletraä)

133.3 mg lopinavir/33.3 mg ritonavir capsules

400 mg lopinavir/100 mg ritonavir/5 ml oral solution

 

        Kaletraä is a co-formulation of the protease inhibitors lopinavir and ritonavir indicated for the treatment of HIV-infection, in combination with other antiretroviral agents.  Ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby increasing the plasma levels of lopinavir.

        Kaletraä should be given with food to enhance bioavailability and minimize pharmacokinetic variability.  Dosing of Kaletraä is shown in the following table:

 

        *Pediatric patients are between 6 months and 12 years of age.

       

        Plasma levels of lopinavir are 15- to 20-fold higher than those of ritonavir after administration of Kaletraä 400 mg/100 mg bid.  Plasma levels of ritonavir are less than 7% of those obtained after administration of ritonavir dose of 600 mg bid, therefore the antiviral activity of Kaletraä is due to lopinavir.  Lopinavir is extensively metabolized by the hepatic CYP3A isozyme.  Ritonavir is a potent inhibitor of CYP3A and was added to the co-formulation to increase levels of lopinavir.  Ritonavir has also been shown to induce metabolic enzymes, resulting in induction of its own metabolism.  Less than 3% of the lopinavir dose is excreted unchanged in the urine.  The half-life of lopinavir over a 12-hour dosing interval averaged 5-6 hours.  Lopinavir pharmacokinetics have not been studied in patients with renal or hepatic insufficiency.  Increases in lopinavir concentrations may be expected in patients with hepatic insufficiency, but not renal insufficiency due to the routes of elimination.

        The most common adverse effect associated with Kaletraä is diarrhea, generally considered mild to moderate.  It has also been associated with abdominal pain, asthenia, nausea, vomiting, headache, and rash.  Pancreatitis has been observed in patients taking Kaletra, patients with a history of pancreatitis may be at increased risk.  The onset or exacerbation of diabetes mellitus/hyperglycemia has been associated with protease inhibitor therapy.

Kaletraä is metabolized by CYP3A isozymes and many other medications may affect its plasma concentrations.  In addition, Kaletraä itself is an inhibitor of CYP3A and to a lesser extent CYP2D6; metabolism of certain medications may be inhibited.  Co-administration of medications that are highly dependent upon CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, is contraindicated.  The following tables display important drug interactions.  The following is not all-inclusive, drug interaction information may also be found in prescribing information or on the Kaletraä website http://www.rxabbott.com/ka/ka003.htm.

 

Drugs that are contraindicated with Kaletra

 

 

 

·        Co-administration with rifampin may lead to loss of virologic response and possible resistance to Kaletraä, to the class of protease inhibitors, or to other co-administered antiretroviral agents.

·        Co-administration with St. John’s wort (Hypericum perforatum) may lead to loss of virologic response to Kaletraä or to the class of protease inhibitors.

·        Lovastatin or simvastatin should NOT be co-administered with Kaletra due to the potential for serious reactions such as risk of myopathy including rhabdomyolysis.

·        Kaletraä induces glucuronidation; therefore, it has the potential to reduce zidovudine and abacavir plasma concentrations.

·        Particular caution should be used when prescribing sildenafil to patients receiving Kaletra since substantially increased concentrations of sildenafil are expected and may result in an increase in sildenafil-related adverse effects such as hypotension, syncope, visual changes, and prolonged erection.

 

Drug interactions with Kaletra: