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Rescriptor

"The child known as the “Mississippi baby””an infant seemingly cured of HIV that was reported as a case study of a prolonged remission of HIV infection in The New England Journal of Medicine last fall”now has detectable levels of HIV after "...

Rescriptor

Side Effects
Interactions

SIDE EFFECTS

The safety of RESCRIPTOR Tablets alone and in combination with other therapies has been studied in approximately 6,000 patients receiving RESCRIPTOR. The majority of adverse events were of mild or moderate (i.e., ACTG Grade 1 or 2) intensity. The most frequently reported drug-related adverse event (i.e., events considered by the investigator to be related to the blinded study medication or events with an unknown or missing causal relationship to the blinded medication) among patients receiving RESCRIPTOR was skin rash (see Table 8 and PRECAUTIONS: Skin Rash).

Table 8: Percent of Patients With Treatment-Emergent Rash in Pivotal Trials (Studies 21 Part II and 13C)a

Percent of Patients With: Description of Rash Gradeb RESCRIPTOR 400 mg t.i.d.
(n = 412)
Control Group Patients
(n = 295)
Grade 1 rash Erythema, pruritus 69 (16.7%) 35 (11.9%)
Grade 2 rash Diffuse maculopapular rash, dry desquamation 59 (14.3%) 17 (5.8%)
Grade 3 rash Vesiculation, moist desquamation, ulceration 18 (4.4%) 0 (0.0%)
Grade 4 rash Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative dermatitis 0 (0.0%) 0 (0.0%)
Rash of any grade   146 (35.4%) 52 (17.6%)
Treatment discontinuation as a result of rash   13 (3.2%) 1 (0.3%)
a Includes events reported regardless of causality.
b ACTG Toxicity Grading System; includes events reported as “rash,” “maculopapular rash,” and “urticaria.”

Adverse events of moderate to severe intensity reported by at least 5% of evaluable patients in any treatment group in the pivotal trials, which includes patients receiving RESCRIPTOR in combination with zidovudine and/or lamivudine in Study 21 Part II for up to 98 weeks and in combination with zidovudine and either lamivudine, didanosine, or zalcitabine in Study 13C for up to 72 weeks are summarized in Table 9.

Table 9: Treatment-Emergent Events Regardless of Causality, of Moderate-to-Severe or Life-Threatening Intensity Reported by at Least 5% of Evaluablea Patients in Any Treatment Group

Adverse Events Study 21 Part II Study 13C
Zidovudine + Lamivudine
(n = 123)
400 mg t.i.d. RESCRIPTOR + Zidovudine
(n = 123)
400 mg t.i.d. RESCRIPTOR + Zidovudine + Lamivudine
(n = 119)
Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 172)
400 mg t.i.d. RESCRIPTOR + Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 170)
% of pts. (n) % of pts. (n) % of pts. (n) % of pts. (n) % of pts. (n)
Body as a Whole
Abdominal pain, generalized 2.4 (3) 3.3 (4) 5.0 (6) 17 (3) 2.4 (4)
Asthenia/fatigue 16.3 (20) 15.4 (19) 16.0 (19) 8.1 (14) 5.3 (9)
Fever 2.4 (3) 1.6 (2) 3.4 (4) 6.4 (11) 7.1 (12)
Flu syndrome 4.9 (6) 7.3 (9) 5.0 (6) 5.2 (9) 2.4 (4)
Headache 14.6 (18) 12.2 (15) 16.8 (20) 12.8 (22) 11.2 (19)
Localized pain 4.9 (6) 5.7 (7) 5.0 (6) 2.9 (5) 1.8 (3)
Digestive
Diarrhea 8.1 (10) 2.4 (3) 4.2 (5) 8.1 (14) 5.9 (10)
Nausea 17.1 (21) 20.3 (25) 16.8 (20) 9.3 (16) 14.7 (25)
Vomiting 8.9 (11) 4.9 (6) 2.5 (3) 4.1 (7) 6.5 (11)
Nervous
Anxiety 1.6 (2) 2.4 (3) 6.7 (8) 4.1 (7) 3.5 (6)
Depressive symptoms 6.5 (8) 4.9 (6) 12.6 (15) 3.5 (6) 5.9 (10)
Insomnia 4.9 (6) 4.9 (6) 5.0 (6) 2.9 (5) 1.2 (2)
Respiratory
Bronchitis 4.1 (5) 6.5 (8) 6.7 (8) 3.5 (6) 3.5 (6)
Cough 9.8 (12) 4.1 (5) 5.0 (6) 5.2 (9) 3.5 (6)
Pharyngitis 6.5 (8) 1.6 (2) 5.0 (6) 4.1 (7) 3.5 (6)
Sinusitis 8.9 (11) 7.3 (9) 5.0 (6) 2.3 (4) 1.2 (2)
Upper respiratory infection 11.4 (14) 6.5 (8) 7.6 (9) 8.7 (15) 4.7 (8)
Skin
Rashes 3.3 (4) 19.5 (24) 13.4 (16) 7.6 (13) 18.8 (32)
aEvaluable patients in Study 21 Part II were those who received at least 1 dose of study medication and returned for at least 1 clinic study visit. Evaluable patients in Study 13C were those who received at least 1 dose of study medication.

Other Adverse Events in Phase II/III Studies: Other adverse events that occurred in patients receiving RESCRIPTOR (in combination treatment) in all Phase II and III studies, considered possibly related to treatment, and of at least ACTG Grade 2 in intensity are listed below by body system.

Body as a Whole: Abdominal cramps, abdominal distention, abdominal pain (localized), abscess, allergic reaction, chills, edema (generalized or localized), epidermal cyst, fever, infection, infection viral, lip edema, malaise, Mycobacterium tuberculosis infection, neck rigidity, sebaceous cyst, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).

Cardiovascular System: Abnormal cardiac rate and rhythm, cardiac insufficiency, cardiomyopathy, hypertension, migraine, pallor, peripheral vascular disorder, and postural hypotension.

Digestive System: Anorexia, bloody stool, colitis, constipation, decreased appetite, diarrhea (Clostridium difficile), diverticulitis, dry mouth, dyspepsia, dysphagia, enteritis at all levels, eructation, fecal incontinence, flatulence, gagging, gastroenteritis, gastroesophageal reflux, gastrointestinal bleeding, gastrointestinal disorder, gingivitis, gum hemorrhage, hepatomegaly, increased appetite, increased saliva, increased thirst, jaundice, mouth or tongue inflammation or ulcers, nonspecific hepatitis, oral/enteric moniliasis, pancreatitis, rectal disorder, sialadenitis, tooth abscess, and toothache.

Hemic and Lymphatic System: Adenopathy, bruising, eosinophilia, granulocytosis, leukopenia, pancytopenia, purpura, spleen disorder, thrombocytopenia, and prolonged prothrombin time.

Metabolic and Nutritional Disorders: Alcohol intolerance, amylase increased, bilirubinemia, hyperglycemia, hyperkalemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hyponatremia, hypophosphatemia, increased AST (SGOT), increased gamma glutamyl transpeptidase, increased lipase, increased serum alkaline phosphatase, increased serum creatinine, and weight increase or decrease.

Musculoskeletal System: Arthralgia or arthritis of single and multiple joints, bone disorder, bone pain, myalgia, tendon disorder, tenosynovitis, tetany, and vertigo.

Nervous System: Abnormal coordination, agitation, amnesia, change in dreams, cognitive impairment, confusion, decreased libido, disorientation, dizziness, emotional lability, euphoria, hallucination, hyperesthesia, hyperreflexia, hypertonia, hypesthesia, impaired concentration, manic symptoms, muscle cramp, nervousness, neuropathy, nystagmus, paralysis, paranoid symptoms, restlessness, sleep cycle disorder, somnolence, tingling, tremor, vertigo, and weakness.

Respiratory System: Chest congestion, dyspnea, epistaxis, hiccups, laryngismus, pneumonia, and rhinitis.

Skin and Appendages: Angioedema, dermal leukocytoclastic vasculitis, dermatitis, desquamation, diaphoresis, discolored skin, dry skin, erythema, erythema multiforme, folliculitis, fungal dermatitis, hair loss, herpes zoster or simplex, nail disorder, petechiae, non-application site pruritus, seborrhea, skin hypertrophy, skin disorder, skin nodule, Stevens-Johnson syndrome, urticaria, vesiculobullous rash, and wart.

Special Senses: Blepharitis, blurred vision, conjunctivitis, diplopia, dry eyes, ear pain, parosmia, otitis media, photophobia, taste perversion, and tinnitus.

Urogenital System: Amenorrhea, breast enlargement, calculi of the kidney, chromaturia, epididymitis, hematuria, hemospermia, impaired urination, impotence, kidney pain, metrorrhagia, nocturia, polyuria, proteinuria, testicular pain, urinary tract infection, and vaginal moniliasis.

Postmarketing Experience

Adverse event terms reported from postmarketing surveillance that were not reported in the Phase II and III trials are presented below.

Digestive System: Hepatic failure.

Hemic and Lymphatic System: Hemolytic anemia.

Musculoskeletal System: Rhabdomyolysis.

Urogenital System: Acute kidney failure.

Laboratory Abnormalities

Marked laboratory abnormalities observed in at least 2% of patients during Studies 21 Part II and 13C are summarized in Table 10. Marked laboratory abnormalities are defined as any Grade 3 or 4 abnormality found in patients at any time during study.

Table 10:Marked Laboratory Abnormalities Reported by ≥ 2% of Patients

Adverse Events/Toxicity Limits Study 21 Part II Study 13C
Zidovudine + Lamivudine
(n =123) % pts.
400 mg t.i.d. RESCRIPTOR + Zidovudine
(n =123) % pts.
400 mg t.i.d. RESCRIPTOR + Zidovudine + Lamivudine
(n = 119) % pts.
Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 172) % pts.
400 mg t.i.d. RESCRIPTOR + Zidovudine + Didanosine, Zalcitabine, or Lamivudine
(n = 170) % pts.
Hematology
Hemoglobin < 7 mg/dL 4.1 2.5 0.9 1.7 2.9
Neutrophils < 750/mm³ 5.7 4.9 3.4 10.4 7.6
Prothrombin time (PT) > 1.5 x ULN 0 0 1.7 2.9 2.4
Activated partial thromboplastin (APTT) > 2.33 x ULN 0 0.8 0 5.8 2.4
Chemistry
Alananine aminotransferase (ALT/SGPT) > 5 x ULN 2.5 4.1 5.1 3.5 4.1
Amylase > 2 x ULN 0.8 2.5 2.6 3.5 2.9
Aspartate aminotransferase (AST/SGOT) > 5 x ULN 1.6 2.5 3.4 3.5 2.3
Bilirubin > 2.5 x ULN 0.8 2.5 1.7 1.2 0
Gamma glutamyl transferase (GGT) > 5 x ULN N/A N/A N/A 4.1 1.8
Glucose (hypo/hyperglycemia) < 40 mg/dL > 250 mg/dL 4.1 0.8 1.7 1.2 0
N/A = not applicable because no predose values were obtained for patients.

Read the Rescriptor (delavirdine mesylate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

(See also CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Drug Interactions.)

Delavirdine is an inhibitor of CYP3A isoform and other CYP isoforms to a lesser extent including CYP2C9, CYP2D6, and CYP2C19. Coadministration of RESCRIPTOR and drugs primarily metabolized by CYP3A (e.g., HMG-CoA reductase inhibitors and sildenafil) may result in increased plasma concentrations of the coadministered drug that could increase or prolong both its therapeutic or adverse effects.

Delavirdine is metabolized primarily by CYP3A, but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. Coadministration of RESCRIPTOR and drugs that induce CYP3A, such as rifampin, may decrease delavirdine plasma concentrations and reduce its therapeutic effect. Coadministration of RESCRIPTOR and drugs that inhibit CYP3A may increase delavirdine plasma concentrations. (See Table 6, Drugs That Should Not Be Coadministered With RESCRIPTOR, and Table 7, Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.)

Table 6: Drugs That Should Not Be Coadministered With RESCRIPTOR

Drug Class: Drug Name Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,a rifampin a May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
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 agent: Cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John's wort (Hypericum perforatum) May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
a See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2.

Table 7: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name Effect on Concentration of Delavirdine or Concomitant Drug Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitor
Didanosinea ↓Delavirdine
↓Didanosine
Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors
NNRTI ↔Delavirdine
↑NNRTI
Combining NNRTIs has not been shown to be beneficial. RESCRIPTOR should not be coadministered with another NNRTI.
HIV-Antiviral Agents: Protease Inhibitors
Indinavira ↑Indinavir A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir ↑Lopinavir
↑Ritonavir
Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavira ↑Nelfinavir
↓Delavirdine
Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established (see CLINICAL PHARMACOLOGY: Tables 1 and 2).
Ritonavir ↑Ritonavir Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavira ↑Saquinavir A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
HIV-Antiviral Agents: CCR5 Inhibitor
Maraviroc ↑Maraviroc Concomitant use of RESCRIPTOR and maraviroc has not been studied. However, RESCRIPTOR is a potent CYP3A4 inhibitor and the maraviroc dose should be reduced during coadministration. Refer to the full prescribing information for maraviroc (SELZENTRY) for dosing recommendations.
Other Agents
Acid blockers: Antacidsa ↓Delavirdine Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole ↓Delavirdine These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines ↑Amphetamines Use with caution.
Antidepressant: Trazodone ↑Trazodone Concomitant use of trazodone and RESCRIPTOR 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 CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiarrhythmics: Bepridil Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone ↑Antiarrhythmics Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin ↑Warfarin It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycina ↑Clarithromycin

When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function:

  • 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 reduced by 75%.
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil ↑Calcium
channel blockers
Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ↓Delavirdine Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil ↑Sildenafil Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin ↑Atorvastatin
↑Cerivastatin
↑Fluvastatin
Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ↑Immunosuppres
sants
Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone ↑Fluticasone Concomitant use of fluticasone and RESCRIPTOR may increase plasma concentrations of fluticasone. Use with caution. Consider alternatives to fluticasone, particularly for long-term use.
Narcotic analgesic: Methadone ↑Methadone Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol ↑Ethinyl estradiol Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.
↑Indicates increase.
↓Indicates decrease.
aThe interaction between RESCRIPTOR and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

Read the Rescriptor Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 8/29/2012
This monograph has been modified to include the generic and brand name in many instances.

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