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Aptivus

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Aptivus

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are described, in greater detail, in other sections:

Due to the need for co-administration of APTIVUS with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials In Adults

APTIVUS, co-administered with ritonavir, has been studied in a total of 6308 HIV-1 positive adults as combination therapy in clinical studies. Of these, 1299 treatment-experienced patients received the dose of 500/200 mg BID. Nine hundred nine (909) adults, including 541 in the 1182.12 and 1182.48 controlled clinical trials, have been treated for at least 48 weeks [see Clinical Studies].

In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent adverse reactions were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain. The 48-Week Kaplan-Meier rates of adverse reactions leading to discontinuation were 13.3% for APTIVUS/ritonavir-treated patients and 10.8% for the comparator arm patients.

Adverse reactions reported in the controlled clinical trials 1182.12 and 1182.48, based on treatment-emergent clinical adverse reactions of moderate to severe intensity (Grades 2 -4) in at least 2% of treatment-experienced subjects in either treatment group are summarized in Table 2 below.

Table 2 : Adverse Reactions Reported in Randomized, Controlled Clinical Trials (1182.12 and 1182.48) Based on Treatment-Emergent Clinical Adverse Reactions of Moderate to Severe Intensity (Grades 2 -4) in at least 2% of Treatment-Experienced Subjects in either Treatment Groupa (48-week Analyses)

  Percentage of patients (rate per 100 patient-exposure years)
APTIVUS/ritonavir (500/200 mg BID) + OBRc (n=749; 757.4 patient-exposure years) Comparator PI/ritonavirb + OBR (n=737; 503.9 patient-exposure years)
Blood and Lymphatic Disorders
  Anemia 3.3% (3.4) 2.3% (3.4)
  Neutropenia 2.0% (2.0) 1.0% (1.4)
Gastrointestinal Disorders
  Diarrhea 15.0% (16.5) 13.4% (21.6)
  Nausea 8.5% (9.0) 6.4% (9.7)
  Vomiting 5.9% (6.0) 4.1% (6.1)
  Abdominal pain 4.4% (4.5) 3.4% (5.1)
  Abdominal pain upper 1.5% (1.5) 2.3% (3.4)
General Disorders
  Pyrexia 7.5% (7.7) 5.4% (8.2)
  Fatigue 5.7% (5.9) 5.6% (8.4)
Investigations
  Weight decreased 3.1% (3.1) 2.2% (3.2)
  ALT increased  2.0% (2.0) 0.5% (0.8)
  GGT increased 2.0% (2.0) 0.4% (0.6)
Metabolism and Nutrition Disorders
  Hypertriglyceridemia 3.9% (4.0) 2.0% (3.0)
  Hyperlipidemia 2.5% (2.6) 0.8% (1.2)
  Dehydration 2.1% (2.1) 1.1% (1.6)
Musculoskeletal and Connective Tissue Disorders
  Myalgia 2.3% (2.3) 1.8% (2.6)
Nervous System Disorders
  Headache 5.2% (5.3) 4.2% (6.3)
  Peripheral neuropathy 1.5% (1.5) 2.0% (3.0)
Psychiatric Disorders
  Insomnia 1.7% (1.7) 3.7% (5.5)
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnea 2.1% (2.1) 1.0% (1.4)
Skin and Subcutaneous Tissue Disorders
  Rash 3.1% (3.1) 3.8% (5.7)
aExcludes laboratory abnormalities that were Adverse Events
bComparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID
cOptimized Background Regimen

Less Common Adverse Reactions

Other adverse reactions reported in < 2% of adult patients (n=1474) treated with APTIVUS/ritonavir 500/200 mg in Phase 2 and 3 clinical trials are listed below by body system:

Blood and Lymphatic System Disorders: thrombocytopenia

Gastrointestinal Disorders: abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis

General Disorders: influenza-like illness, malaise

Hepatobiliary Disorders: hepatitis, hepatic failure, hyperbilirubinemia, cytolytic hepatitis, toxic hepatitis, hepatic steatosis

Immune System Disorders: hypersensitivity

Investigations: hepatic enzymes increased, liver function test abnormal, lipase increased

Metabolism and Nutrition Disorders: anorexia, decreased appetite, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity

Musculoskeletal and Connective Tissue Disorders: muscle cramp

Nervous System Disorders: dizziness, intracranial hemorrhage, somnolence

Psychiatric Disorders: sleep disorder

Renal and Urinary Disorders: renal insufficiency

Skin and Subcutaneous System Disorders: exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus

Laboratory Abnormalities

Treatment-emergent laboratory abnormalities reported at 48 weeks in the controlled clinical trials 1182.12 and 1182.48 in adults are summarized in Table 3 below.

Table 3 : Treatment-Emergent Laboratory Abnormalities Reported in ≥ 2% of Adult Patients (48-week Analyses)

  Limit Randomized, Controlled Clinical Trials 1182.12 and 1182.48
Percentage of Patients (rate per 100 patient-exposure years)
APTIVUS/ritonavir (500/200 mgBID) + OBR
(n=738)
Comparator PI/ritonavir + OBR*
(n=724)
Hematology
  WBC count decrease
    Grade 3  < 2.0 x 103/μL 5.4% (5.6) 4.8% (7.7)
    Grade 4 < 1.0 x 103/μL 0.3% (0.3) 1.1% (1.7)
Chemistry
  Amylase
    Grade 3 > 2.5 x ULN 5.7% (5.9) 6.4% (10.4)
    Grade 4 > 5 x ULN 0.3% (0.3) 0.7% (1.1)
  ALT
    Grade 2 > 2.5-5 x ULN 14.9% (16.5) 7.5% (12.4)
    Grade 3 > 5-10 x ULN 5.6% (5.7) 1.7% (2.6)
    Grade 4 > 10 x ULN 4.1% (4.1) 0.4% (0.7)
  AST
    Grade 2 > 2.5-5 x ULN 9.9% (10.5) 8.0% (13.3)
    Grade 3 > 5-10 x ULN 4.5% (4.6) 1.4% (2.2)
    Grade 4 > 10 x ULN 1.6% (1.6) 0.4% (0.6)
  ALT and/or AST
    Grade 2-4 > 2.5 x ULN 26.0% (31.5) 13.7% (23.8)
  Cholesterol
    Grade 2 > 300 - 400 mg/dL 15.6% (17.7) 6.4% (10.5)
    Grade 3 > 400 - 500 mg/dL 3.3% (3.3) 0.3% (0.4)
    Grade 4 > 500 mg/dL 0.9% (1.0) 0.1% (0.2)
  Triglycerides
    Grade 2 400 - 750 mg/dL 35.9% (49.9) 26.8% (51.0)
    Grade 3 > 750 - 1200 mg/dL 16.9% (19.4) 8.7% (14.6)
    Grade 4 > 1200 mg/dL 8.0% (8.4) 4.3% (7.0)
*Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID

In controlled clinical trials 1182.12 and 1182.48 extending up to 96 weeks, the proportion of patients who developed Grade 2-4 ALT and/or AST elevations increased from 26% at week 48 to 32.1% at week 96 with APTIVUS/ritonavir. The risk of developing transaminase elevations is greater during the first year of therapy.

Clinical Trials In Pediatric Patients

APTIVUS, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-na´ve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs.

The adverse reactions profile seen in Study 1182.14 was similar to adults. Pyrexia (6.4%), vomiting (5.5%), cough (5.5%), rash (5.5%), nausea (4.5%), and diarrhea (3.6%) were the most frequently reported adverse reactions (Grade 2-4, all causes) in pediatric patients. Rash was reported more frequently in pediatric patients than in adults.

The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%).

Due to previous reports of both fatal and non-fatal intracranial hemorrhage (ICH), an analysis of bleeding events was performed. At 48 weeks of treatment, the frequency of pediatric patients with any bleeding adverse reactions was 7.5%. No drug related serious bleeding adverse reaction was reported. The most frequent bleeding adverse reaction was epistaxis (3.7%). No other bleeding adverse reaction was reported in frequency of > 1%. Additional trial follow-up through 100 weeks showed a cumulative 12% frequency of any bleeding adverse reaction.

Read the Aptivus (tipranavir) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

See also CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY.

Potential For APTIVUS/ritonavir To Affect Other Drugs

APTIVUS co-administered with ritonavir at the recommended dose 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 APTIVUS/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 [see CONTRAINDICATIONS]. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring.

Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below.

A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of APTIVUS/ritonavir capsule administration on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP 3A4/5 (midazolam) and Pglycoprotein (P-gp) (digoxin). This study determined the first-dose and steady-state effects of 500 mg of APTIVUS co-administered with 200 mg of ritonavir twice daily in capsule form. APTIVUS oral solution co-administered with ritonavir capsules demonstrated similar effects as APTIVUS capsules co-administrated with ritonavir.

There was no net effect on CYP 2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP 1A2, but there was moderate induction at steady state. There was modest inhibition of CYP 2C19 at the first dose, but there was marked induction at steady state. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4/5 activities were observed after first dose and steady state.

Intestinal and hepatic P-gp activity was assessed by administering oral and intravenous digoxin, respectively. The digoxin results indicate P-gp was inhibited after the first dose of APTIVUS/ritonavir followed by induction of P-gp over time. Thus, it is difficult to predict the net effect of APTIVUS administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the coadministered drugs for CYP 3A and P-gp, and the extent of intestinal first-pass metabolism/efflux. An in vitro induction study in human hepatocytes showed an increase in UGT1A1 by tipranavir similar to that evoked by rifampin. The clinical consequences of this finding have not been established.

Potential For Other Drugs To Affect Tipranavir

Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of APTIVUS/ritonavir and drugs that induce CYP 3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations. Co-administration of APTIVUS/ritonavir with drugs that inhibit CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of APTIVUS/ritonavir 500/200 mg twice daily.

Clinically significant drug-drug interactions of APTIVUS co-administered with ritonavir are summarized in Table 4 below.

Table 4 : 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-1 Antiviral Agents
Fusion Inhibitors: Enfuvirtide ↑Tipranavir At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended.
Non-Nucleoside Reverse Transcriptase Inhibitors:
Etravirine ↓Etravirine APTIVUS/ritonavir when coadministered with etravirine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine. Etravirine and APTIVUS/ritonavir should not be coadministered.
Rilpivirine The use of rilpivirine co-administered with APTIVUS/ritonavir has not been studied. Concomitant use of rilpivirine with Aptivus/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of Aptivus/ritonavir.
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 APTIVUS/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):
Fosamprenavir Lopinavir Saquinavir ↓Amprenavir
↓Lopinavir
↓Saquinavir
Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.
Protease Inhibitors (co-administered with 100 mg of ritonavir):
Atazanavir ↓Atazanavir
↑Tipranavir
 
Virus Integrase Strand Transfer Inhibitors:
Raltegravir ↓Raltegravir APTIVUS/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended.
Agents for Opportunistic Infections
Antifungals:
Fluconazole Itraconazole Ketoconazole Voriconazole ↑Tipranavir, ↔ Fluconazole
↑ Itraconazole (not studied)
↑Ketoconazole (not studied)
⇓ Voriconazole (not studied)
Fluconazole increases tipranavir 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.
Antimycobacterials:
Clarithromycin ↑Tipranavir, ↑Clarithromycin, ↓14-hydroxy-clarithromycin metabolite No dose adjustment of APTIVUS 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
Anticonvulsants:
Carbamazepine Phenobarbital Phenytoin ↓ Tipranavir Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly.
Valproic Acid ↓Valproic Acid Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly.
Antidepressants:
Trazodone ↑Trazodone Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Desipramine Combination with APTIVUS/ritonavir not studied ↑Desipramine Dosage reduction and concentration monitoring of desipramine is recommended.
Selective Serotonin-Reuptake Inhibitors: Combination with APTIVUS/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
 
Anti-HCV agents
Boceprevir Co-administration of APTIVUS and boceprevir has not been studied. With concomitant use, changes in exposure were observed both for boceprevir and certain protease inhibitors used for the treatment of HIV-1 infection or either medication. Information is not available regarding tipranavir or boceprevir exposure with concomitant use. It is not recommended to co-administer boceprevir with APTIVUS/ritonavir.
Telaprevir Co-administration of APTIVUS and telaprevir has not been studied. With concomitant use, changes in exposure were observed both for telaprevir and certain protease inhibitors used for the treatment of HIV-1 infection or telaprevir. Information is not available regarding tipranavir or telaprevir exposure with concomitant use. It is not recommended to co-administer telaprevir with APTIVUS/ritonavir.
Anti-gout
Colchicine
↑Colchicine In patients with renal or hepatic impairment, coadministration of colchicine in patients on APTIVUS/ritonavir is contraindicated.
In combination with APTIVUS/ritonavir, the following dosage adjustments are recommended in patients with normal renal and hepatic function: Treatment of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir:
  • 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir:
  • If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
  • If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): Co-administration of colchicine in patients on APTIVUS/ritonavir:
  • Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antipsychotics:
Quetiapine Combination with APTIVUS/ritonavir not studied Concomitant use of quetiapine and APTIVUS/ritonavir may alter plasma concentrations of quetiapine. If quetiapine is concomitantly administered with APTIVUS/ritonavir, more frequent monitoring of the clinical response to quetiapine as well as potential adverse events is recommended.
Benzodiazepines:
Parenterally administered midazolam ↑Midazolam Midazolam is extensively metabolized by CYP 3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, APTIVUS should not be given with orally administered midazolam [see CONTRAINDICATIONS]. If APTIVUS is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustments should be considered.
Buprenorphine/naloxone ↔  Buprenorphine
↓ Tipranavir
APTIVUS/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir Cmin was decreased approximately 40% with this combination. Dose adjustments cannot be recommended.
Calcium Channel Blockers: Diltiazem Felodipine Nicardipine Nisoldipine Verapamil Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP3A and P-gp due to conflicting effect of TPV/ritonavir on CYP3A and P-gp.
⇓Diltiazem
↑ Felodipine (CYP3A substrate but not Pgp substrate)
⇓Nicardipine
⇓ Nisoldipine (CYP3A 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).
Endothelin receptor antagonists   Co-administration of bosentan in patients on APTIVUS/ritonavir:
Bosentan ↑Bosentan

In patients who have been receiving APTIVUS/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of APTIVUS/ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of APTIVUS/ritonavir.
After at least 10 days following the initiation of APTIVUS/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors:
Atorvastatin Rosuvastatin ↑Atorvastatin
↓Hydroxy-atorvastatin metabolites
↑Rosuvastatin
Avoid co-administration with atorvastatin.
Hypoglycemics:
  Combination with APTIVUS/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 substrate is not known.
 
Immunosuppressants: Cyclosporine Sirolimus Tacrolimus Combination with APTIVUS/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
Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended.
Inhaled beta agonist:
Salmeterol ↑Salmeterol Concurrent administration of APTIVUS/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
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. Coadministration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic Analgesics:
Meperidine Combinations with APTIVUS/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
↓S-Methadone,
↓ R-Methadone
Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir.
Oral Contraceptives/Estrogens:
Ethinyl estradiol ↓ Ethinyl estradiol concentrations by 50% Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS 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.
Proton Pump Inhibitors:
Omeprazole ↓Omeprazole, ↔Tipranavir with APTIVUS and ritonavir.
PDE-5 Inhibitors:
Sildenafil Tadalafil Vardenafil Only the combination of tadalafil with APTIVUS/ritonavir has been studied (at doses used for treatment of erectile dysfunction).
↑Sildenafil (not studied)
↑ Tadalafil with first dose APTIVUS/ritonavir
↔Tadalafil at APTIVUS/ritonavir steady-state
↑ Vardenafil (not studied)
Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
  • Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see CONTRAINDICATIONS].
  • The following dose adjustments are recommended for use of tadalafil (Adcirca) with APTIVUS/ritonavir:
Co-administration of tadalafil (Adcirca) in patients on APTIVUS/ritonavir:
In patients receiving APTIVUS/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of APTIVUS/ritonavir in patients on tadalafil (Adcirca):
Avoid use of tadalafil (Adcirca) during the initiation of APTIVUS/ritonavir. Stop Adcirca at least 24 hours prior to starting APTIVUS/ritonavir. After at least one week following the initiation of APTIVUS/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
Concomitant use of PDE-5 inhibitors with APTIVUS/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
Use with increased monitoring for adverse events.
Warfarin ↔S-Warfarin Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy.
↑ increase, ↓ decrease, ↔ no change, ⇓ unable to predict

Last reviewed on RxList: 4/18/2014
This monograph has been modified to include the generic and brand name in many instances.

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