Aptivus (Tipranavir) - Warnings and Precautions

WARNINGS

ALERT: Find out about medicines that should NOT be taken with APTIVUS®. This statement is included on the product's bottle label.

APTIVUS (tipranavir) must be co-administered with 200 mg of ritonavir to exert its therapeutic effect (see DOSAGE AND ADMINISTRATION). Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions (effect of tipranavir and ritonavir on other drugs).

Please refer to ritonavir prescribing information for additional information on precautionary measures.

Intracranial Hemorrhage

APTIVUS, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS.

Effects on Platelet Aggregation and Coagulation

APTIVUS/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see ANIMAL PHARMACOLOGY AND TOXICOLOGY).

Hepatic Impairment and Toxicity

APTIVUS co-administered with 200 mg of ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment.

Patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2.5-fold risk for developing further transaminase elevations or hepatic decompensation. Additionally, Grade 3 and 4 increases in hepatic transaminases were observed in 6% of healthy volunteers in Phase 1 studies and 6% of subjects receiving APTIVUS/ritonavir in Phase 3 studies.

Tipranavir is principally metabolized by the liver. Therefore caution should be exercised when administering APTIVUS/ritonavir to patients with hepatic impairment because tipranavir concentrations may be increased. APTIVUS/ritonavir is contraindicated in patients with moderate to severe (Child-Pugh Class B and Child-Pugh Class C) hepatic insufficiency.

Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation.

For information on the multi-dose pharmacokinetics of tipranavir in hepatically impaired patients see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Hepatic Impairment.

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Drug Interactions

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of APTIVUS/ritonavir and fluticasone propionate may produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see PRECAUTIONS, Drug Interactions).

Particular caution should be used when prescribing phosphodiesterase (PDE5) inhibitors for erectile dysfunction (e.g., sildefafil, tadalafil, or vardenafil) in patients receiving protease inhibitors, including APTIVUS. Co-administration of a protease inhibitor with PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS, Drug Interactions and Information for Patients, and the complete specific PDE5 inhibitor prescribing information).

PRECAUTIONS

Sulfa Allergy

APTIVUS (tipranavir) should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir is unknown.

Rash

Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in subjects receiving APTIVUS/ritonavir. In Phase 2 and 3 trials rash was observed in 14% of females and in 8-10% of males receiving APTIVUS/ritonavir. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by APTIVUS/ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving APTIVUS/ritonavir (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS).

Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established.

Lipid Elevations

Treatment with APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides (see ADVERSE REACTIONS, Table 11). Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate (see PRECAUTIONS, Drug Interactions, Table 9: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with APTIVUS/ritonavir and HMG-CoA reductase inhibitors).

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tipranavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jeroveci pneumonia, tuberculosis, or reactivation of herpes simplex and herpes zoster), which may necessitate further evaluation and treatment.

Information for Patients

Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage.

Patients should report any unusual or unexplained bleeding to their physician.

Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir, has been associated with severe liver disease, including some deaths. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. Symptoms of hepatitis include fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Extra vigilance is needed for patients with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity.

Liver function tests should be performed prior to initiating therapy with tipranavir and 200 mg of ritonavir, and frequently throughout the duration of treatment. Patients with chronic hepatitis B or C co-infection or elevations in liver enzymes prior to treatment are at increased risk (approximately 2.5-fold) for developing further liver enzyme elevations or severe liver disease. Caution should be exercised when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients. APTIVUS should not be given to patients with moderate to severe liver disease.

Mild to moderate rash has been reported in HIV-infected men and women receiving APTIVUS/ritonavir.

Women receiving estrogen-based hormonal contraceptives should be instructed that additional or alternative contraceptive measures should be used during therapy with APTIVUS/ritonavir. There may be an increased risk of rash when APTIVUS is given with hormonal contraceptives.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

Patients should be informed that APTIVUS must be co-administered with 200 mg ritonavir to ensure its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect.

Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using APTIVUS. Patients should be advised to take APTIVUS and other concomitant antiretroviral therapy every day as prescribed. APTIVUS, co-administered with ritonavir, must be given in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of APTIVUS is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.

Patients should be informed that APTIVUS is not a cure for HIV-1 infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of APTIVUS are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with APTIVUS can reduce the risk of transmitting HIV to others through sexual contact.

APTIVUS may interact with some drugs; therefore, patients should be advised to report to their health care provider the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.

APTIVUS should be taken with food to enhance absorption.

The Patient Package Insert provides written information for the patients, and should be dispensed with each new prescription and refill.

Drug Interactions

Tipranavir administered with ritonavir can alter plasma exposure of other drugs and other drugs can alter plasma exposure of tipranavir and ritonavir.

Tipranavir co-administered with 200 mg of ritonavir at the recommended dosage is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of tipranavir/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring (see CONTRAINDICATIONS and PRECAUTIONS).

The mechanisms of the potential interactions are described in the CLINICAL PHARMACOLOGY, Drug Interactions section.

Drugs that are contraindicated or not recommended for co-administration with APTIVUS are included in Table 8 below. These recommendations are based on either drug interaction studies or they are predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 8 Drugs that Should Not be Co-administered with APTIVUS Co-administered with 200 mg of Ritonavir

Drug Class/Drug Name	Clinical Comment
Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics.
Antihistamines Astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials Rifampin	May lead to loss of virologic response and possible resistance to tipranavir or to the class of protease inhibitors.
Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agents Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal products St. John's wort	May lead to loss of virologic response and possible resistance to tipranavir or to the class of protease inhibitors.
HMG CoA reductase inhibitors Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptics Pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedatives/hypnotics Midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

Clinically significant drug-drug interactions of APTIVUS co-administered with 200 mg of ritonavir are summarized in Table 9 below.

Table 9 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug name	Effect on Concentration of Tipranavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Nucleoside reverse transcriptase inhibitors:
Abacavir	↓ Abacavir AUC by approximately 40%	Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.
Didanosine (EC)	↓ Didanosine	Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from TPV/ritonavir dosing by at least 2 hours.
Zidovudine	↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered.	Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease inhibitors (co-administered with 200 mg of ritonavir):		Combining amprenavir, lopinavir or saquinavir with APTIVUS/ritonavir is not recommended. No formal drug interaction data are currently available for the concomitant use of APTIVUS, co-administered with 200 mg of ritonavir, with protease inhibitors other than those listed above.
Amprenavir Lopinavir Saquinavir	↓ Amprenavir, ↓ Lopinavir, ↓ Saquinavir
Other Agents for Opportunistic Infections
Antifungals:		Fluconazole increases TPV concentrations but dose adjustments are not needed. Fluconazole doses > 200 mg/day are not recommended. Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (200 mg/day) are not recommended. Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction.
Fluconazole Itraconazole Ketoconazole Voriconazole	↑ Tipranavir, ↔ Fluconazole ↑ Itraconazole (not studied) ↑ Ketoconazole (not studied) ↨Voriconazole (not studied)
Antimycobacterials:
Clarithromycin	↑ Tipranavir, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycin metabolite	No dose adjustment of tipranavir or clarithromycin for patients with normal renal function is necessary. For patients with renal impairment the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR< 30 mL/min the dose of clarithromycin should be decreased by 75%.
Rifabutin	Tipranavir not changed, ↑Rifabutin ↑ Desacetyl-rifabutin	Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g. 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary.
Other Agents Commonly used
Antidepressants:
Trazadone	↑ Trazadone	Concomitant use of trazadone and APTIVUS/ritonavir may increase plasma concentrations of trazadone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazadone and ritonavir. If trazadone is used with a CYP3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazadone should be considered.
Desipramine	Combination with TPV/ritonavir not studied ↑ Desipramine	Dosage reduction and concentration monitoring of desipramine is recommended.
Selective Serotonin-Reuptake Inhibitors:	Combination with TPV/ritonavir not studied	Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.
Fluoxetine Paroxetine Sertraline	↑ Fluoxetine ↑ Paroxetine ↑ Sertraline
Calcium Channel Blockers: Diltiazem Felodipine Nicardipine Nisoldipine Verapamil	Combination with TPV/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP 3A and P-gp due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. ↨Diltiazem ↑ Felodipine (CYP 3A substrate but not P-gp substrate) ↨Nicardipine ↨Nisoldipine (CYP 3A substrate but not clear whether it is a P-gp substrate) ↨Verapamil	Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/Metronidazole	Combination with TPV/ritonavir not studied	APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g. metronidazole).
HMG-CoA reductase inhibitors:		Start with the lowest possible dose of atorvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors. Concomitant use of APTIVUS, co-administered with 200 mg of ritonavir, with lovastatin or simvastatin is not recommended.
Atorvastatin	↑ Tipranavir, ↑ Atorvastatin ↓ Hydroxy-atorvastatin metabolites
Hypoglycemics:	Combination with TPV/ritonavir not studied.	Careful glucose monitoring is warranted.
Glimepiride Glipizide Glyburide Pioglitazone Repaglinide Tolbutamide	↨Glimepiride (CYP 2C9) ↨Glipizide (CYP 2C9) ↨Glyburide (CYP 2C9) ↨Pioglitazone (CYP 2C8 and CYP 3A4) ↨Repaglinide (CYP 2C8 and CYP 3A4) ↨Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8 and CYP 2C9 substrates is not known.
Immunosuppressants: Cyclosporine Sirolimus Tacrolimus	Combination with TPV/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. ↨Cyclosporine ↨Sirolimus ↨Tacrolimus	More frequent concentration monitoring of these medicinal products is recommended until blood levels have been stabilized.
Inhaled /nasal steroids: Fluticasone	↑ Fluticasone	Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS).
Narcotic analgesics:
Meperidine	Combinations with TPV/ritonavir not studied ↓ Meperidine, ↑ Normeperidine	Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g. seizures).
Methadone	↓ Methadone by 50%	Dosage of methadone may need to be increased when co-administered with tipranavir and 200 mg of ritonavir.
Oral contraceptives/Estrogens:		Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with tipranavir and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non serious rash.
Ethinyl estradiol	↓ Ethinyl estradiol concentrations by 50%
PDE5 inhibitors: Sildenafil Tadalafil Vardenafil	Combinations with TPV/ritonavir not studied. ↑ Sildenafil ↑ Tadalafil ↑ Vardenafil	Concomitant use of PDE5 inhibitors with tipranavir and ritonavir should be used with caution and in no case should the starting dose of: sildenafil exceed 25 mg within 48 hours tadalafil exceed 10 mg every 72 hours vardenafil exceed 2.5 mg every 72 hours
Warfarin	Combination with TPV/ritonavir not studied. Cannot predict the effect of TPV/ritonavir on S-Warfarin due to conflicting effect of TPV and RTV on CYP 2C9	Frequent INR (international normalized ratio) monitoring upon initiation of tipranavir/ritonavir therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term animal carcinogenicity bioassays with tipranavir and tipranavir/ritonavir are currently in progress. However, tipranavir showed no evidence of mutagenicity or clastogenicity in a battery of five in vitro and in vivo tests including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, unscheduled DNA synthesis in rat hepatocytes, induction of gene mutation in Chinese hamster ovary cells, a chromosome aberration assay in human peripheral lymphocytes, and a micronucleus assay in mice.

Tipranavir had no effect on fertility or early embryonic development in rats at dose levels up to 1000 mg/kg/day, equivalent to a C_max of 258 μM in females. Based on C_max levels in these rats, as well as an exposure (AUC) of 1670 μM·h in pregnant rats from another study, this exposure was approximately equivalent to the anticipated exposure in humans at the recommended dose level of 500/200 mg tipranavir/ritonavir BID.

Pregnancy

Teratogenic Effects, Pregnancy Category C.

Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats.

No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 μM·h or approximately 0.8-fold human exposure at the recommended dose. In rats and rabbits, fetal toxicity was not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, corresponding accordingly to C_max/AUC_0-24h levels of 30.4 μM/340 μM·h and 8.4 μM/120 μM·h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose.

In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day (~0.8-fold human exposure). No post-weaning functions were affected at any dose level.

There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. APTIVUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to APTIVUS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and any possible adverse effects of tipranavir, mothers should be instructed not to breastfeed if they are receiving APTIVUS.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of APTIVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of APTIVUS in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.