"Two phase 3 sister studies assessing the efficacy and safety of the dapivirine vaginal ring for the prevention of HIV-1 will likely be among the most-watched clinical trial results presented here at the Conference on Retroviruses and Opportu"...
The following adverse reactions are described, in greater detail, in other sections:
- Hepatic Impairment and Toxicity [see WARNINGS AND PRECAUTIONS]
- Intracranial Hemorrhage [see WARNINGS AND PRECAUTIONS]
- Rash [see WARNINGS AND PRECAUTIONS]
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
|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)|
|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)|
|Pyrexia||7.5% (7.7)||5.4% (8.2)|
|Fatigue||5.7% (5.9)||5.6% (8.4)|
|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)|
|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
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
Immune System Disorders: hypersensitivity
Investigations: hepatic enzymes increased, liver function test abnormal, lipase increased
Musculoskeletal and Connective Tissue Disorders: muscle cramp
Nervous System Disorders: dizziness, intracranial hemorrhage, somnolence
Psychiatric Disorders: sleep disorder
Renal and Urinary Disorders: renal insufficiency
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)
|Randomized, Controlled Clinical Trials 1182.12 and 1182.48|
|Percentage of Patients (rate per 100 patient-exposure years)|
|Limit||APTIVUS/ ritonavir (500/200 mgBID) + OBR
|Comparator PI/ritonavir + OBR*
|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)|
|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)|
|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)|
|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)|
|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)|
|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
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 steadystate 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):|
|Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.|
|Protease Inhibitors (co-administered with 100 mg of ritonavir):|
|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|
↑ 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.
|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:
|Rifabutin||Tipranavir not changed, ↑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|
|↓ 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.|
|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
|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.|
|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 eout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir:
|Quetiapine||↑ Quetiapine||Initiation of APTIVUS with ritonavir in patients taking auetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
Initiation of quetiapine in patients taking APTIVUS with ritonavir:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
|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.|
|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
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.
|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|
|Bosentan||↑Bosentan||Co-administration of bosentan in patients on APTIVUS/ritonavir:
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:|
↓ Hydroxy-atorvastatin metabolites
|Avoid co-administration with atorvastatin.|
|Combination with APTIVUS/ritonavir not studied ↔ 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.
|Careful glucose monitoring is warranted.|
|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
|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.|
|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.|
|Meperidine||Combinations with APTIVUS/ritonavir not
↓ 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).|
↓ S-Methadone, ↓ R-Methadone
|Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir.|
|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||Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.|
|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
↔ Tadalafil at APTIVUS/ritonavir steadystate
↑ 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):
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:
|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: 4/27/2015
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