Rescriptor

Name: Rescriptor

Rescriptor Precautions

Some side effects can be serious. If you experience any of the following symptoms, stop taking Rescriptor and call your doctor immediately or get emergency medical treatment:

  • rash along with other symptoms such as fever, blistering, sores in the mouth, red or swollen eyes, or muscle or joint pain
  • hives
  • itching
  • swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
  • hoarseness
  • difficulty breathing or swallowing

Rescriptor can interact with many medications. These interactions could cause serious side effects that could cause death. Before you take Rescriptor, you must tell your healthcare provider about all the medicines you are taking or are planning to take. These include other prescription and nonprescription medicines and herbal supplements.

Rescriptor can cause drowsiness. Do not drive or operate heavy machinery until you know how Rescriptor affects you.

Do not take Rescriptor if you:

  • are allergic to Rescriptor or to any of its ingredients
  • if you are taking certain medicines (see "Drug Interactions")

Rescriptor and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Rescriptor Usage

  • You should stay under a healthcare provider's care when taking Rescriptor. Do not change your treatment or stop treatment without first talking with your healthcare provider.
  • You must take Rescriptor every day exactly as your healthcare provider prescribed it. Follow the directions from your healthcare provider, exactly as written on the label.
  • The usual dose of Rescriptor is two 200 mg tablets three times a day or four 100 mg tablets three times a day, in combination with other anti-HIV medicines. Either way, your total daily dose of Rescriptor remains the same.
  • You can take Rescriptor with or without food.
  • If you have trouble swallowing tablets, the 100 mg Rescriptor tablets may be dissolved in water. Place four tablets in at least 3 ounces of water and allow the tablets to sit in the water for a few minutes. Then, stir the water until the tablets have dissolved and drink the mixture right away. Add a little more water, swirl, and then drink the rest of the mixture to be sure that you get all the medicine. The 200 mg tablets must be swallowed whole. They cannot be dissolved in water.
  • Many people find it easier to take their Rescriptor with breakfast, lunch, and dinner, since food does not interfere with Rescriptor. It is a good idea to get into the habit of taking Rescriptor on a regular schedule to make it easier to remember. Figure out things that happen every day at pill-taking time and take your tablets then. By taking your medicine along with activities you do every day, such as getting up in the morning, brushing your teeth, eating lunch, coming home from work in the evening, or watching a favorite TV show, you will find it easier to remember to take every dose.
  • When your Rescriptor supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to Rescriptor and become harder to treat.
  • Only take medicine that has been prescribed specifically for you. Do not give Rescriptor to others or take medicine prescribed for someone else.

If you forget to take a dose of Rescriptor, take it as soon as possible. However, if you skip the dose entirely, do not double the next dose. If you forget a lot of doses, talk to your healthcare provider about how you should continue taking your medicine.

What should I discuss with my healthcare provider before taking Rescriptor (delavirdine)?

You should not use delavirdine if you are allergic to it.

Some medicines can interact with delavirdine and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

  • alprazolam (Xanax);

  • carbamazepine;

  • lovastatin;

  • midazolam;

  • phenytoin;

  • phenobarbital;

  • pimozide;

  • rifabutin;

  • rifampin;

  • simvastatin (Zocor, Vytorin);

  • St. John's wort;

  • triazolam; or

  • ergot medicine--dihydroergotamine, ergotamine, ergonovine, methylergonovine.

Using any of these medicines while you are taking delavirdine can cause serious medical problems or death.

To make sure delavirdine is safe for you, tell your doctor if you have:

  • liver or kidney disease;

  • high cholesterol or triglycerides;

  • low stomach acid production; or

  • if you have ever taken any HIV medication that was not effective in treating your condition.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Rescriptor (delavirdine) side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using delavirdine and call your doctor at once if you have a severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Delavirdine may increase your risk of certain infections or autoimmune disorders by changing the way your immune system works. Symptoms may occur weeks or months after you start treatment with delavirdine. Tell your doctor if you have:

  • signs of a new infection--fever, night sweats, swollen glands, mouth sores, diarrhea, stomach pain, weight loss;

  • chest pain (especially when you breathe), dry cough, wheezing, feeling short of breath;

  • cold sores, sores on your genital or anal area;

  • rapid heart rate, feeling anxious or irritable, weakness or prickly feeling, problems with balance or eye movement;

  • trouble speaking or swallowing, severe lower back pain, loss of bladder or bowel control; or

  • swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence, loss of interest in sex.

Common side effects may include:

  • mild skin rash;

  • nausea, diarrhea;

  • feeling tired;

  • headache; or

  • changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Rescriptor Dosage and Administration

Administration

Oral Administration

Administer orally 3 times daily with or without food.1

For patients unable to swallow tablets, 100-mg tablets may be administered as slurry or dispersion in water.1 To prepare dispersion containing 400 mg, place four 100-mg tablets in a glass containing ≥90 mL of water, let stand for a few minutes, then stir until a uniform dispersion occurs.1 6 Consume dispersion promptly; rinse glass with more water and swallow the rinse.1

The 200-mg tablets are not readily dispersed in water1 33 and should be swallowed intact.1

Patients with achlorhydria should take delavirdine with an acidic beverage (e.g., orange or cranberry juice).1

Dosage

Available as delavirdine mesylate; dosage expressed in terms of delavirdine mesylate.1

Pediatric Patients

Treatment of HIV Infection Oral

Adolescents ≥16 years of age: 400 mg 3 times daily.1

Adults

Treatment of HIV Infection Oral

400 mg 3 times daily.1

Special Populations

Hepatic Impairment

Data insufficient to make dosage recommendation for patients with hepatic impairment;200 use with caution.1 200

Renal Impairment

Dosage adjustments not needed.200

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Cautions for Rescriptor

Contraindications

  • Known hypersensitivity to delavirdine or any ingredient in the formulation.1

  • Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alprazolam, cisapride, ergot alkaloids, midazolam, pimozide, triazolam).1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Interactions

Concomitant use with certain drugs not recommended (e.g., lovastatin, simvastatin, rifampin, rifabutin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) or requires particular caution (sildenafil).1 (See Specific Drugs under Interactions.)

Sensitivity Reactions

Dermatologic Reactions

Severe rash, erythema multiforme, Stevens-Johnson syndrome reported; these severe reactions resolved after drug discontinued.1

Patients experiencing severe rash or rash accompanied by fever, blistering, oral lesions, conjunctivitis, swelling, or muscle or joint aches should discontinue delavirdine and seek medical assistance.1

Mild rash also reported.1 Rash usually occurs during first month of therapy, mainly on upper body and proximal arms with decreasing intensity of lesions on neck and face and progressively less on rest of trunk and limbs.1

Rash usually resolves in <2 weeks and generally does not require dosage reduction or contraindicate use of the drug.1 If delavirdine therapy is interrupted because of rash, most patients are able to resume therapy with the drug.1

Mild or moderate rash can be treated with diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.1

General Precautions

HIV Resistance

Possibility of HIV resistant to delavirdine and possible cross-resistance to other NNRTIs.1

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance reported in patients receiving antiretroviral therapy.1 Mechanisms and long-term consequences unknown; causal relationship not established.1

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; time to onset is variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

Category C.1

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Safety and efficacy not established in children <16 years of age.1

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Extensively metabolized in liver; use with caution in those with hepatic impairment.1

Common Adverse Effects

Rash, asthenia/fatigue, nausea.1

Rescriptor Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract; peak plasma concentrations achieved within 1 hour.1

Bioavailability of delavirdine tablets is 85% relative to that of an oral solution of the drug.1 Bioavailability of 100-mg tablets is increased by approximately 20% when allowed to disintegrate in water and administered as a slurry.1

Food

Food does not have an appreciable effect on plasma concentrations or AUC.1

Distribution

Extent

Not fully characterized.1

Distributed into CSF in low concentrations.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

98%.1

Elimination

Metabolism

Metabolized by CYP3A and CYP2D6.1

Elimination Route

Excreted in feces (44%) and urine (51%).1

Half-life

5.8 hours.1

Description of clinical studies

For clinical Studies 21 Part II and 13C described below, efficacy was evaluated by the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL through Week 52 as measured by the Roche Amplicor® HIV-1 Monitor (standard assay). An intent-to-treat analysis was performed where only subjects who achieved confirmed suppression and sustained it through Week 52 are regarded as responders. All other subjects (including never suppressed, discontinued, and those who rebounded after initial suppression of <400 copies/mL) are considered failures at Week 52. Results of an interim analysis of efficacy conducted for studies 21 Part II and 13C by independent Data and Safety Monitoring Boards (DSMBs) revealed that the triple-therapy arms in both studies produced significantly greater antiviral benefit than the dual-therapy arms, and early termination of the studies was recommended.

Study 21 Part II

Study 21 Part II was a double‑blind, randomized, placebo‑controlled trial comparing treatment with Rescriptor (400 mg 3 times daily, zidovudine 200 mg 3 times daily, and lamivudine 150 mg twice daily versus Rescriptor 400 mg 3 times daily and zidovudine 200 mg 3 times daily versus zidovudine 200 mg 3 times daily and lamivudine 150 mg twice daily in 373 HIV-1–infected patients (mean age 35 years [range: 17 to 67], 87% male, and 60% Caucasian) who were antiretroviral treatment naive (84%) or had limited nucleoside experience (16%). Mean baseline CD4+ cell count was 359 cells/mm3 and mean baseline plasma HIV‑1 RNA was 4.4 log10 copies/mL.

Results showed that the mean increases from baseline in CD4 cell counts at 52 weeks were 111 cells/mL for Rescriptor + zidovudine + lamivudine, 27 cells/mL for Rescriptor + zidovudine, and 74 cells/mL for zidovudine + lamivudine.

The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL are presented in Figure 1. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 52 weeks are summarized in Table 3. Subjects who were never suppressed before discontinuation were placed in the discontinuation category.

Figure 1. Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 21 Part II: Intent-to–Treat Analysis

Table 3. Outcomes of Randomized Treatment Through Week 52 for Protocol 21 Part II



Outcome

Zidovudine + Lamivudine
(n = 124)
%

Rescriptor + Zidovudine
(n = 125)
%

Rescriptor + Zidovudine + Lamivudine
(n = 124)
%

HIV-1 RNA <400 copies/mLa

14

2

45

HIV-1 RNA ≥400 copies/mLb,c

64

52

31

Discontinued due to adverse eventsc

8

13

10

Discontinued due to other reasonsc,d

14

33

14

aCorresponds to rates at Week 52 in proportion curve.

bVirologic failures at or before Week 52.

cConsidered to be treatment failure in the analysis.

d Includes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons.

Study 13C

Study 13C was a double‑blind, randomized, placebo‑controlled trial comparing treatment with Rescriptor 400 mg 3 times daily, zidovudine 200 mg 3 times daily or 300 mg twice daily, and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily versus zidovudine 200 mg 3 times daily or 300 mg twice daily and either didanosine 200 mg twice daily, zalcitabine 0.75 mg 3 times daily, or lamivudine 150 mg twice daily in 345 HIV-1–infected patients (mean age 35.8 years [range: 18 to 72], 66% male, and 63% Caucasian) who were antiretroviral treatment naive (63%) or had limited antiretroviral experience (37%). Mean baseline CD4+ cell count was 210 cells/mm3 and mean baseline plasma HIV‑1 RNA was 4.9 log10 copies/mL.

Results showed that the mean increases from baseline in CD4+ cell counts at 54 weeks were 102 cells/mL for Rescriptor + zidovudine + didanosine or zalcitabine or lamivudine, and 56 cells/mL for zidovudine + didanosine or zalcitabine or lamivudine.

The results of the intent‑to‑treat analysis of the percentage of patients with a plasma HIV‑1 RNA level 400 copies/mL are presented in Figure 2. HIV‑1 RNA status and reasons for discontinuation of randomized treatment at 54 weeks are summarized in Table 4. Subjects who were never suppressed before discontinuation were placed in the discontinuation category.

Figure 2. Percentage of Patients With HIV-1 RNA Below 400 copies/mL Standard PCR Assay Protocol 13C: Intent-to–Treat Analysis

Table 4. Outcomes of Randomized Treatment Through Week 54 for Protocol 13C

Outcome

Zidovudine + Didanosine or Zalcitabine or Lamivudine
(n = 173)
%

Zidovudine + Didanosine or Zalcitabine or Lamivudine + Rescriptor
(n = 172)
%

HIV‑1 RNA 400 copies/mLa

10

29

HIV‑1 RNA 400 copies/mLb,c

69

42

Discontinued due to adverse eventsc

7

12

Discontinued due to other reasonsc,d

14

17

aCorresponds to rates at Week 54 in proportion curve.

bVirologic failures at or before Week 54.

cConsidered to be treatment failure in the analysis.

dIncludes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons.

Results from several smaller supportive studies evaluating the use of Rescriptor in treatment-naive patients suggest that it may have activity when used in combination with protease inhibitors and NRTIs in 3- or 4-drug combinations.

Precautions

General

Delavirdine is metabolized primarily by the liver. Therefore, caution should be exercised when administering Rescriptor Tablets to patients with impaired hepatic function.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Rescriptor. During the initial phase of the combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Resistance/Cross-Resistance

NNRTIs, when used alone or in combination, may confer cross-resistance to other NNRTIs.

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.

Skin Rash

Severe rash, including rare cases of erythema multiforme and Stevens-Johnson syndrome, has been reported in patients receiving Rescriptor. Erythema multiforme and Stevens-Johnson syndrome were rarely seen in clinical trials and resolved after withdrawal of Rescriptor. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue Rescriptor and consult a physician. Two cases of Stevens-Johnson syndrome have been reported through postmarketing surveillance out of a total of 339 surveillance reports.

In Studies 21 Part II and 13C (see  DESCRIPTION OF CLINICAL STUDIES), rash (including maculopapular rash) was reported in more patients who were treated with Rescriptor 400 mg 3 times daily (35% and 32%, respectively) than in those who were not treated with Rescriptor (21% and 16%, respectively). The highest intensity of rash reported in these studies was severe (Grade 3), which was observed in approximately 4% of patients treated with Rescriptor in each study and in none of the patients who were not treated with Rescriptor. Also in Studies 21 Part II and 13C, discontinuations due to rash were reported in more patients who received Rescriptor 400 mg 3 times daily (3% and 4%, respectively) than in those who did not receive Rescriptor (0% and 1%, respectively).

In most cases, the duration of the rash was less than 2 weeks and did not require dose reduction or discontinuation of Rescriptor. Most patients were able to resume therapy after rechallenge with Rescriptor following a treatment interruption due to rash. The distribution of the rash was mainly on the upper body and proximal arms, with decreasing intensity of the lesions on the neck and face, and progressively less on the rest of the trunk and limbs.

Occurrence of a delavirdine-associated rash after 1 month is uncommon. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.

Information for Patients

A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with Rescriptor. A patient package insert (PPI) for Rescriptor is available for patient information.

Patients should be informed that Rescriptor is not a cure for HIV‑1 infection and that patients may continue to experience illnesses associated with HIV‑1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician while taking Rescriptor.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment. • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. • Do not breastfeed. We do not know if Rescriptor can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Patients should be instructed that the major toxicity of Rescriptor is rash and should be advised to promptly notify their physician should rash occur. The majority of rashes associated with Rescriptor occur within 1 to 3 weeks after initiating treatment with Rescriptor. The rash normally resolves in 3 to 14 days and may be treated symptomatically while therapy with Rescriptor is continued. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue medication and consult a physician.

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 to take Rescriptor every day as prescribed. Patients should not alter the dose of Rescriptor without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose.

Patients with achlorhydria should take Rescriptor with an acidic beverage (e.g., orange or cranberry juice). However, the effect of an acidic beverage on the absorption of delavirdine in patients with achlorhydria has not been investigated.

Patients taking both Rescriptor and antacids should be advised to take them at least 1 hour apart.

Because Rescriptor may interact with certain drugs, patients should be advised to report to their doctor the use of any prescription, nonprescription medication, or herbal products, particularly St. John’s wort.

Patients receiving sildenafil and Rescriptor should be advised that they may be at an increased risk of sildenafil‑associated adverse events, including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor.

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.

aSee 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

↑Antiarrhythmics

Use with caution. Increased bepridil exposure may be associated with life‑threatening reactions such as cardiac arrhythmias.

Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone

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

↑Immunosuppressants

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Delavirdine was negative in a battery of genetic toxicology tests which included an Ames assay, an in vitro  rat hepatocyte unscheduled DNA synthesis assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, an in vitro mutation assay in Chinese hamster ovary cells, and an in vivo micronucleus test in mice.

Lifetime carcinogenicity studies were conducted in rats at doses of 10, 32, and 100 mg/kg/day and in mice at doses of 62.5, 250, and 500 mg/kg/day for males and 62.5, 125, and 250 mg/kg/day for females. In rats, delavirdine was noncarcinogenic at maximally tolerated doses that produced exposures (AUC) up to 12 (male rats) and 9 (female rats) times human exposure at the recommended clinical dose. In mice, delavirdine produced significant increases in the incidence of hepatocellular adenoma/adenocarcinoma in both males and females, hepatocellular adenoma in females, and mesenchymal urinary bladder tumors in males. The systemic drug exposures (AUC) in female mice were 0.5- to 3-fold and in male mice 0.2- to 4-fold of those in humans at the recommended clinical dose. Given the lack of genotoxic activity of delavirdine, the relevance of urinary bladder and hepatocellular neoplasm in delavirdine-treated mice to humans is not known.

Delavirdine at doses of 20, 100, and 200 mg/kg/day did not cause impairment of fertility in rats when males were treated for 70 days and females were treated for 14 days prior to mating.

Pregnancy

Pregnancy Category C. Delavirdine has been shown to be teratogenic in rats. Delavirdine caused ventricular septal defects in rats at doses of 50, 100, and 200 mg/kg/day when administered during the period of organogenesis. The lowest dose of delavirdine that caused malformations produced systemic exposures in pregnant rats equal to or lower than the expected human exposure to Rescriptor (Cmin 15 μM) at the recommended dose. Exposure in rats approximately 5-fold higher than the expected human exposure resulted in marked maternal toxicity, embryotoxicity, fetal developmental delay, and reduced pup survival. Additionally, reduced pup survival on postpartum day 0 occurred at an exposure (mean Cmin) approximately equal to the expected human exposure. Delavirdine was excreted in the milk of lactating rats at a concentration 3 to 5 times that of rat plasma.

Delavirdine at doses of 200 and 400 mg/kg/day administered during the period of organogenesis caused maternal toxicity, embryotoxicity, and abortions in rabbits. The lowest dose of delavirdine that resulted in these toxic effects produced systemic exposures in pregnant rabbits approximately 6-fold higher than the expected human exposure to Rescriptor (Cmin 15 μM) at the recommended dose. The no-observed-adverse-effect dose in the pregnant rabbit was 100 mg/kg/day. Various malformations were observed at this dose, but the incidence of such malformations was not statistically significantly different from that observed in the control group. Systemic exposures in pregnant rabbits at a dose of 100 mg/kg/day were lower than those expected in humans at the recommended clinical dose. Malformations were not apparent at 200 and 400 mg/kg/day; however, only a limited number of fetuses were available for examination as a result of maternal and embryo death.

No adequate and well-controlled studies in pregnant women have been conducted. Rescriptor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Of 9 pregnancies reported in premarketing clinical studies and postmarketing experience, a total of 10 infants were born (including 1 set of twins). Eight of the infants were born healthy. One infant was born HIV-positive but was otherwise healthy and with no congenital abnormalities detected, and 1 infant was born prematurely (34 to 35 weeks) with a small muscular ventricular septal defect that spontaneously resolved. The patient received approximately 6 weeks of treatment with delavirdine and zidovudine early in the course of the pregnancy.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Rescriptor and other antiretroviral agents, 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 reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Rescriptor.

Pediatric Use

Safety and effectiveness of delavirdine in combination with other antiretroviral agents have not been established in HIV-1–infected individuals younger than 16 years of age.

Geriatric Use

Clinical studies of Rescriptor 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 taken when dosing Rescriptor in elderly patients due to the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Animal Toxicology

Toxicities among various organs and organ systems in rats, mice, rabbits, dogs, and monkeys were observed following the administration of delavirdine. Necrotizing vasculitis was the most significant toxicity that occurred in dogs when mean nadir serum concentrations of delavirdine were at least 7-fold higher than the expected human exposure to Rescriptor (Cmin 15 μM) at the recommended dose. Vasculitis in dogs was not reversible during a 2.5-month recovery period; however, partial resolution of the vascular lesion characterized by reduced inflammation, diminished necrosis, and intimal thickening occurred during this period. Other major target organs included the gastrointestinal tract, endocrine organs, liver, kidneys, bone marrow, lymphoid tissue, lung, and reproductive organs.

Manufactured for

ViiV Healthcare

Research Triangle Park, NC 27709

by

Pfizer Pharmaceuticals LLC

Vega Baja, Puerto Rico 00693

©2012, ViiV Healthcare. All rights reserved.

August 2012

RES: 3PI

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