Product Monograph - Rescriptor
ACTION AND CLINICAL PHARMACOLOGY
RESCRIPTOR (delavirdine mesylate) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of the human immunodeficiency virus-type 1 (HIV-1). Reverse transcriptase (RT) is located in the core of the HIV-1 virus and is released upon entry into the host cell. It uses the viral RNA as a template to form DNA. This is a pivotal step in the HIV-1 infection process.
Delavirdine mesylate (henceforth referred to as delavirdine) is a selective inhibitor of RT. It binds directly to RT and blocks RNA-dependent and DNA-dependent DNA polymerase activities.
Delavirdine does not compete with template: primer or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine.
In vitro HIV-1 susceptibility
The antiviral activity of delavirdine in vitro has been demonstrated in both acute and chronic HIV infections in lymphoblastic and monocytic cell lines and peripheral blood lymphocytes with laboratory and clinical isolates of HIV-1. IC50 and IC90 values (50% and 90% inhibitory concentrations) for laboratory isolates (N=5) ranged from 0.005 to 0.030 µM and 0.04 to 0.10 µM, respectively. Mean IC50 of clinical isolates (N=74) was 0.038 µM (range 0.001 to 0.69 µM); 73 of 74 clinical isolates had an IC50 ≤ 0.18 µM. The IC90 of 24 of these clinical isolates ranged from 0.05 to
0.10 µM. In drug combination studies of delavirdine with zidovudine, didanosine, zalcitabine, lamivudine, interferon- α and protease inhibitors, additive to synergistic anti-HIV-1 activity was observed in cell culture. The relationship between the in vitro susceptibility of HIV-1 RT inhibitors and inhibition of HIV replication in humans has not been established.
Drug resistance
Phenotypic analysis of isolates from patients treated with delavirdine as monotherapy showed a 50-fold to 500-fold reduction in sensitivity in 14 of 15 patients by Week 8 of therapy. Genotypic analysis of HIV-1 isolates from patients receiving delavirdine plus zidovudine combination therapy
(n=79) showed resistance conferring mutations in all isolates by Week 24 of therapy. In delavirdine treated patients the mutations in RT occurred predominantly at amino acid positions 103 and less frequently at position 181 and 236. In a separate study, an average of 86-fold increase in zidovudine susceptibility of patient isolates (n=24) was observed after 24-weeks of delavirdine and zidovudine combination therapy. The clinical relevance of the phenotypic and the genotypic changes associated with delavirdine therapy has not been established.
Cross-resistance
NNRTIs, when used alone or in combination, may confer cross-resistance to other NNRTIs.
Pharmacokinetics (see PHARMACOLOGY-Pharmacokinetics)
The pharmacokinetic properties of delavirdine have been studied in healthy volunteers and in HIV-1–infected patients after single oral doses of delavirdine ranging from 10 mg to 400 mg and after multiple oral doses ranging from 20 mg tid to 850 mg tid.
Pharmacokinetic parameters of delavirdine after multiple dosing of delavirdine tablets 400 mg tid are shown below.
Mean +/- Standard Deviation (Range) Steady-State Pharmacokinetic Parameters in HIV-1
Infected Patients (N=67) after 400 mg tid.
| Cmin (µM) | 15± 10 (0.1-45) |
| Cmax (µM) | 35± 20 (2-100) |
| AUC (µM●hr) | 180 ± 100 (5-515) |
| Tmax (hr) | 1.3 ± 0.7 (0.5-5) |
| T1/2 (hr) | 5.8 ± 2.5* (2-13) |
*n=54
Special Populations
Hepatic or Renal Impairment: The pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated (see PRECAUTIONS).
Gender: Data from population pharmacokinetics suggest that the plasma concentrations of delavirdine tend to be higher in females than in males. However, this difference is not considered to be clinically significant.
Race: No significant differences in the pharmacokinetics of delavirdine were observed between different racial or ethnic groups.
Age: The pharmacokinetics of delavirdine have not been adequately studied in patients <16 years or
>65 years of age.
Drug Interactions
Specific drug interaction studies were performed with delavirdine and a number of drugs. Table 1 summarizes the effect of delavirdine on the geometric mean AUC, Cmax and Cmin of coadministered drugs. Table 2 shows the effects of coadministered drugs on the geometric mean AUC, Cmax and
Cmin of delavirdine.
For information regarding clinical recommendations, see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions.
Table 1. Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Delavirdine
| Coadministered Drug | Dose of Coadministered Drug | Dose of RESCRIPTOR | n | % Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI) | ||
| Cmax | AUC | Cmin | ||||
| HIV-Protease Inhibitors | ||||||
| Nelfinavir | 750 mg tid x 14 days | 400 mg tid x 7 days | 12 | ↑88 (↑66- ↑113) | ↑107 (↑83 - ↑135) | ↑136 (↑103- ↑175) |
750 mg tid x 28 days | 400 mg tid x 28 days | 22 | ↑63* (↑28 - ↑106 ) | ↑74* (↑38 - ↑120) | ↑83* (↑40 -↑138) | |
| Indinavir | 600 or 800 mg tid x 7 days | 0 or 400 mg tid x 7 days | 28 | ↔** | ↑53** (↑7 - ↑120) | ↑298** (↑104 - ↑678 ) |
600 mg Single- Dose | 400 mg tid x 10 days | 14 | ↓18† (↓25 - ↓10) | ↑45† (↑30 - ↑62) | - | |
| Saquinavir | Hard gel capsule 600 mg tid x 21 days | 400 mg tid x 14 days | 13 | ↑317 (↑187- ↑504 ) | ↑348 (↑215 - ↑535 ) | ↑376 (↑256- ↑535) |
| Soft gel capsule 1000 or 1200 mg tid x 28 days | 0 or 400 mg tid x 28 days | 20 | ↑98‡ (↑4- ↑277) | ↑121‡ (↑14 - ↑340 ) | ↑199‡ (↑37- ↑553) | |
| Ritonavir | 600 mg bid for >35 days | 400 mg tid x 21 days | 12 | ↑54 (↑24 - ↑91) | ↓51 (↓24 - ↓83) | ↑76 (↑50 - ↑105) |
| Nucleoside Reverse Transcriptase Inhibitors | ||||||
| Zidovudine | 200 mg tid for >38 days | 100 mg qid to 400 mg tid for 8-10 days | 34 | ↔ | ↔ | - |
| Didanosine (buffered tablets) | 125 or 250 mg bid x 28 days | 400 mg tid x 28 days | 9 | ↓20§ (↓44 -↓15) | ↓21§ (↓40 - ↓5) | - |
| Anti-infective Agents | ||||||
| Rifabutin | 300 mg od for 15- 99 days | 400-1000 mg tid for 45-129 days | 5 | ↑128 (↑71 - ↑203 ) | ↑230 (↑199 - ↑396) | ↑452 (↑246 - ↑781) |
| Clarithromycin | 500 mg bid x 15 days | 300 mg tid x 30 days | 6 | _ | ↑100 | _ |
↑Indicates increase ↓Indicates decrease ↔Indicates no significant change
*Percent change based on a comparison to historical data.
**Indinavir 600 mg tid plus RESCRIPTOR 400 mg tid relative to indinavir 800 mg tid without RESCRIPTOR. †Indinavir 600 mg single-dose plus RESCRIPTOR 400 mg tid relative to indinavir 800 mg single-dose alone. ‡Saquinavir soft gel capsule 1000 mg tid plus RESCRIPTOR 400 mg tid relative to saquinavir soft gel capsule 1200 mg tid without RESCRIPTOR
§RESCRIPTOR taken with didanosine (buffered tablets) relative to doses of RESCRIPTOR and didanosine separated by at least 1 hr.
- Indicates no data is available.
Table 2. Pharmacokinetic Parameters for Delavirdine in the Presence of Coadministered Drugs
Coadministered Drug | Dose of Coadministered Drug | Dose of RESCRIPTOR | n | % Change in Delavirdine Pharmacokinetic Parameters (90% CI) | ||
| Cmax | AUC | Cmin | ||||
| HIV-Protease Inhibitors | ||||||
| Indinavir | 600 mg Single- Dose | 400 mg tid x 10 days | 14 | ↔ | ↔ | ↔ |
0 or 600 mg tid x 7 days | 400 mg tid x 7 days | 81 | ↔* | ↔* | ↔* | |
| Nelfinavir | 750 mg tid x 7 days | 400 mg tid x 14 days | 7 | ↓27 (↓49- ↑4 ) | ↓31 (↓57- ↑10 ) | ↓33 (↓70- ↑49) |
750 mg tid x 28 days | 400 mg tid x 28 days | 77 | ↓38* (↓57- ↓10) | ↓35* (↓57- ↓1) | 49* (↓70 - ↓12 ) | |
| Ritonavir | 0 or 600 mg bid for >35 days | 400 mg tid for 7- 21 days | 25 | ↔* | ↔* | ↔* |
| Saquinavir | Hard gel capsule 600 mg tid x 14 days | 400 mg tid x 28 days | 7 | ↔* | ↔* | ↔* |
Soft gel capsule 0 or 1000 mg tid x 28 days | 400 mg tid for 7- 28 days | 23 | ↔* | ↔* | ↔* | |
| Nucleoside Reverse Transcriptase Inhibitors | ||||||
| Zidovudine | 0 or 200 mg tid for > 7 days | 400 mg tid for 7- 14 days | 42 | ↔* | ↔* | ↔* |
| Didanosine (buffered tablets) | 125 or 250 mg bid x 28 days | 400 mg tid x 28 days | 9 | ↓32† (↓48- ↓11) | ↓19† (↓37- ↑6) | ↔† |
Coadministered Drug | Dose of Coadministered Drug | Dose of RESCRIPTOR | n | % Change in Delavirdine Pharmacokinetic Parameters (90% CI) | ||
| Cmax | AUC | Cmin | ||||
| Anti-infective Agents | ||||||
| Clarithromycin | 500 mg bid x 15 days | 300 mg tid x 30 days | 6 | ↔ | ↔ | ↔ |
| Fluconazole | 400 mg od x 15 days | 300 mg tid x 30 days | 8 | ↔ | ↔ | ↔ |
| Ketoconazole | Various | 200-400 mg tid | 26 | - | - | ↑50‡ |
| Rifampin | 600 mg od x 15 days | 400 mg tid x 30 days | 7 | ↓90 (↓94 - ↓83 ) | ↓97 (↓98- ↓95 ) | ↓100 |
| Rifabutin | 300 mg od x 14 days | 400 mg tid x 28 days | 7 | ↓72 (↓61- ↓80) | ↓82 (↓74- ↓88) | ↓94 (↓90-↓96) |
| Sulfamethoxazole or Trimethoprim & Sulfamethoxazole | Various | 200-400 mg tid | 311 | - | - | ↔‡ |
| Other | ||||||
| Antacid (Maalox® TC) | 20 mL | 300 mg Single- Dose | 12 | ↓52 (↓68 - ↓29) | ↓44 (↓58 - ↓27) | - |
| Fluoxetine | Various | 200-400 mg tid | 36 | - | - | ↑50‡ |
| Phenytoin, Phenobarbital, Carbamazepine | Various | 300-400 mg tid | 8 | - | - | ↓90‡ |
↑Indicates increase.
↓Indicates decrease.
↔Indicates no significant change.
*Percent change based on a comparison to historical data.
†RESCRIPTOR taken with didanosine (buffered tablets) relative to doses of RESCRIPTOR and didanosine separated by at least 1 hr.
‡Population pharmacokinetic data from efficacy studies.
- Indicates no data is available.
INDICATIONS AND CLINICAL USE
RESCRIPTOR (delavirdine mesylate) is indicated for the treatment of HIV-1 infection in highly customized antiretroviral regimens, in patients who are likely to be intolerant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs).
This indication is based on the modest antiretroviral efficacy shown in clinical trials in antiretroviral-naive patients, when RESCRIPTOR was used in combination with two other nucleoside reverse transcriptase inhibitors (NRTIs), compared to two NRTIs alone. There are insufficient data directly comparing RESCRIPTOR-containing antiretroviral regimens with currently preferred multi-drug regimens for treatment of HIV infection. There is no controlled clinical trial evidence for use of
RESCRIPTOR in rescue-therapy regimens.
Resistant viruses emerge rapidly when RESCRIPTOR is used as monotherapy. Therefore,
RESCRIPTOR should always be used in combination with at least two other appropriate antiretroviral agents. Non-nucleoside reverse transcriptase inhibitors, when used alone or in combination, may confer cross-resistance to other NNRTIs.
CONTRAINDICATIONS
RESCRIPTOR (delavirdine mesylate) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulation.
Coadministration of RESCRIPTOR is contraindicated with drugs that are highly dependent on
CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 3. Also, see PRECAUTIONS, Table 4,
Drugs That Should Not Be Coadministered With RESCRIPTOR.
| Table 3. Drugs That Are Contraindicated With RESCRIPTOR | |
| Drug Class | Drugs Within Class That Are Contraindicated With RESCRIPTOR |
| Ergot derivatives | Dihydroergotamine, ergonovine, ergotamine, methylergonovine |
| Neuroleptic | Pimozide |
| Sedative/hypnotics | Alprazolam, midazolam, triazolam |
WARNINGS
Drug Interactions
Delavirdine may inhibit the metabolism of many different drugs (eg, antiarrhythmics, calcium channel blockers, sedative hypnotics, and others), serious and/or life threatening drug interactions could result from inappropriate coadministration of some drugs with delavirdine. In addition, some drugs may markedly reduce delavirdine plasma concentrations, resulting in suboptimal antiviral activity and subsequent emergence of drug resistance. All prescribers should become familiar with the following tables in this monograph: Table 3, Drugs That Are Contraindicated With
RESCRIPTOR; Table 5, Established and Other Potentially Significant Drug Interactions:
Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or
Predicted Interaction. Additional details on drug interactions can be found in Tables 1 and 2 under the CLINICAL PHARMACOLOGY section.
Concomitant use of lovastatin or simvastatin with RESCRIPTOR is not recommended. Caution should be exercised if RESCRIPTOR is used concurrently with other HMG-CoA reductase inhibitors
(statins) that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin) or CYP2C9 pathway
(e.g., fluvastatin). The risk of myopathy including rhabdomyolysis may be increased when
RESCRIPTOR is used in combination with these drugs.
Particular caution should be used when prescribing sildenafil in patients receiving RESCRIPTOR.
Coadministration of sildenafil with RESCRIPTOR is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes and priapism (see PRECAUTIONS, Drug Interactions and Information for Patients, and the complete Prescribing Information for sildenafil).
Concomitant use of St. John’s wort (hypericum perforatum) or St. John’s wort containing products and RESCRIPTOR is not recommended. Coadministration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including RESCRIPTOR, is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of RESCRIPTOR and lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
PRECAUTIONS
Hepatic Impairment:
Delavirdine is metabolized primarily by the liver. Therefore, caution should be exercised when administering RESCRIPTOR (delavirdine mesylate) to patients with impaired hepatic function.
Resistance/Cross-Resistance:
Non-nucleoside reverse transcriptase inhibitors, when used alone or in combination, may confer cross-resistance to other non-nucleoside reverse transcriptase inhibitors.
Skin Rash:
Patients may experience a skin rash, which is usually temporary. Skin rash attributable to
RESCRIPTOR has occurred in 18% of all patients on combination regimens in phase II and III controlled trials who received RESCRIPTOR 400 mg tid. Dose titration does not significantly reduce the incidence of rash. Skin rash is more common in patients with lower CD4 cell counts and typically occurs within 1 to 3 weeks of treatment.
Severe and life threatening skin reactions have occurred on rare occasions in patients treated with RESCRIPTOR, including Stevens-Johnson syndrome and erythema multiforme. None of them were associated with fatalities. RESCRIPTOR must be discontinued in patients developing a severe rash or a rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, or general malaise. As there are currently insufficient data on patients who have had a skin reaction to nevirapine or efavirenz and were further treated with
RESCRIPTOR, close monitoring of these patients is recommended. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.
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.
Pregnancy:
No adequate and well-controlled studies in pregnant women have been conducted. Since delavirdine has been shown to be teratogenic in rats (see TOXICOLOGY), 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 six weeks of treatment with delavirdine and zidovudine early in the course of 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 or via the internet at http://www.apregistry.com.
Nursing Mothers:
It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether delavirdine is excreted in human milk. Since delavirdine has been found to be excreted in the milk of lactating rats (see TOXICOLOGY), mothers should be instructed not to breast-feed their babies if they are receiving RESCRIPTOR.
Pediatric Use:
Safety and effectiveness of RESCRIPTOR has 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.
Drug Interactions (see also CONTRAINDICATIONS, WARNINGS, AND CLINICAL
PHARMACOLOGY-Pharmacokinetics-Drug Interactions):
Delavirdine is an inhibitor of CYP3A4 isoform and other 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 effect 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 reduce 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 4, Drugs That Should Not Be Coadministered With RESCRIPTOR, and
Table 5, Established and Other Potentially Significant Drug Interactions: Alteration in Dose or
Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.)
Table 4. 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 non-nucleoside reverse transcriptase inhibitors. |
| Antimycobacterials: rifabutin*, rifampin* | May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors 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. |
Herbal Products: St. John’s wort (hypericum perforatum) | May lead to loss of virologic response and possibly resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors. |
| 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. |
*See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2.
Table 5. 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 | ||
| Amprenavir | ↑ Amprenavir | Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established. |
| Didanosine* | ↓ Delavirdine ↓ Didanosine | Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least one hour. |
| Indinavir* | ↑ Indinavir | A dose reduction of indinavir to 600 mg tid 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. |
| Nelfinavir* | ↑ 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. |
| Saquinavir* | ↑ 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. |
| Other Agents | ||
Acid blockers: Antacids* H2 Receptor Antagonists: cimetidine, famotidine, nizatidine, ranitidine Proton Pump Inhibitors: omeprazole, lansoprazole | ↓ Delavirdine | Doses of an antacid and RESCRIPTOR should be separated by at least one hour, because the absorption of delavirdine is reduced when coadministered with antacids. |
| 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 | ↑ Amphetamine | Use with caution. |
| 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: clarithromycin* | ↑ 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%. |
Dihydropyridine Calcium Channel Blockers: amlodipine, diltiazem, felodipine, nifedipine, nimodipine, verapamil | ↑ Dihydropyridine 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 Agent: sildenafil | ↑ Sildenafil | Sildenafil should not exceed a maximum single dose of 25 mg in 48 hour period. |
HMG-CoA Reductase Inhibitors: atorvastatin, 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 | ↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR. |
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
*See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2. Information to be Provided to the Patient:
Patients should be informed that RESCRIPTOR is not a cure for HIV-1 infection, and that they may continue to acquire illnesses associated with HIV-1 infection, including opportunistic infections.
Treatment with RESCRIPTOR has not been shown to reduce the incidence or frequency of such illnesses, and patients should be advised to remain under the care of a physician when using
RESCRIPTOR.
Patients should be advised that the use of RESCRIPTOR has not been shown to reduce the risk of transmission of HIV-1.
Patients should be instructed that the major toxicity of RESCRIPTOR is rash and should be advised to promptly notify their physician should a 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, muscle or joint aches should be advised to 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 (eg, 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 one hour apart.
Because RESCRIPTOR may interact with certain drugs, patients should be advised to report to their doctor the use of any prescription and non-prescription medications 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.
Patients taking RESCRIPTOR as a dispersion, should rinse the glass with water and swallow the rinse to ensure that the entire dose is consumed.
ADVERSE REACTIONS
The safety of RESCRIPTOR (delavirdine mesylate) alone and in combination with other antiretroviral therapies has been studied in patients in combination with nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors. The majority of adverse events were of mild or moderate intensity. The most frequently reported drug-related adverse event (i.e., an event considered by the investigator to be related to the blinded study medication, or an event with an unknown or missing causal relationship to the blinded medication) among patients receiving
RESCRIPTOR was skin rash (see Table 6 and PRECAUTIONS-Skin Rash).
Table 6. Percent of Patients With Treatment-Emergent Rash in Pivotal Trials
(Studies 21 Part II and 13C)*
| Percent of Patients with: | Description of Rash Grade§ | RESCRIPTOR 400 mg TID (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%) |
*Includes rash reported regardless of causality.
§ACTG Toxicity Grading System; includes events reported as “rash”, “maculopapular rash” and “urticaria”.
Adverse events of moderate (ACTG grade 2) to severe (ACTG grade 3) 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 7.
Table 7. Treatment-Emergent Adverse Events, Regardless of Causality, of Moderate-to-Severe or Life-Threatening Intensity Reported by at Least 5% of Evaluable* Patients in Any Treatment Group.
| Study 21 Part II | Study 13C | ||||
Adverse Events
| ZDV + 3TC (N=123) | 400 mg tid RESCRIPTOR + ZDV (N=123) | 400 mg tid RESCRIPTOR + ZDV + 3TC (N=119) | ZDV + ddI, ddC, or 3TC (N=172) | 400 mg tid RESCRIPTOR + ZDV + ddI, ddC or 3TC (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) | 1.7 (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) |
*Evaluable patients in Study 21 Part II were those who received at least one dose of study medication and returned for at least one clinic study visit. Evaluable patients in Study 13C were those who received at least one dose of study medication.
Other adverse events that occurred in patients receiving RESCRIPTOR (in combination treatment) in all phase II/III studies, and considered possibly related to treatment and of at least ACTG grade 2 (moderate) 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, pain (generalized), redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution) and sebaceous cyst.
Cardiovascular: Abnormal cardiac rate and rhythm, cardiac insufficiency, cardiomyopathy, hypertension, migraine, pallor, peripheral vascular disorder, and postural hypotension.
Gastrointestinal: 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 haemorrhage, hepatomegaly, increased appetite, increased saliva, increased thirst, jaundice, mouth or tongue inflammation or ulcers, nonspecific hepatitis, oral/enteric monilia, pancreatitis, rectal disorder, sialadenitis, tooth abscess, and toothache.
Haemic and Lymphatic: Adenopathy, bruising, eosinophilia, granulocytosis, leukopenia, pancytopenia, purpura, spleen disorder, thrombocytopenia, and prolonged prothrombin time.
Metabolic and Nutritional Disorders: Alcohol intolerance, amylase increased, bilirubinemia, hypergylcemia, 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: Arthralgia or arthritis of single and multiple joints, bone disorder, bone pain, myalgia, tendon disorder, tenosynovitis, tetany, and vertigo.
Nervous: 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: Chest congestion, dyspnea, epistaxis, hiccups, laryngismus, pneumonia, and rhinitis.
Skin and Appendages: Angioedema, dermal leukocytoclastic vasculitis, dermatitis, desquamation, diaphoresis, discoloured skin, dry skin, erythema, erythema multiforme, folliculitis, fungal dermatitis, hair loss, herpes zoster or simplex, maculopapular rash, nail disorder, petechiae, non-application site pruritus, seborrhea, skin disorder, skin hypertrophy, skin nodule, Stevens-Johnson syndrome, urticaria, vesiculobullous rash, and wart.
Special Senses: Blepharitis, blurred vision, conjunctivitis, diplopia, dry eyes, ear pain, parosmia, photophobia, taste perversion, and tinnitus.
Urogenital: 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 by body system:
Digestive: Hepatic failure.
Hemic and Lymphatic: Hemolytic anemia.
Musculoskeletal: Rhabdomyolysis.
Skin Rash: Stevens-Johnson syndrome and erythema multiforme.
Urogenital: Acute kidney failure.
Laboratory Abnormalities:
Marked laboratory abnormalities observed in at least 2% of patients during therapy in Studies 21 Part
II and 13C are summarized in Table 8. Marked laboratory abnormalities are defined as a two-gradeshift from baseline to a Grade 3 and 4 abnormality in a patient at any time during study.
Table 8. Marked Laboratory Abnormalities Reported by ≥ 2% of Patients
| Study 21 Part II | Study 13C | |||||
| Toxicity Limit | ZDV + 3TC N=123 | 400 mg tid RESCRIPTOR + ZDV N=123 | 400 mg tid RESCRIPTOR + ZDV + 3TC N=119 | ZDV + ddI, ddC or 3TC N=172 | 400 mg tid RESCRIPTOR + ZDV + ddI, ddC or 3TC N=170 | |
| % pts. | % pts. | % pts. | % pts. | % 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 amino- transferase (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 amino- transferase (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/hyper- glycemia) | <40 mg/dL >250 mg/dL | 4.1 | 0.8 | 1.7 | 1.2 | 0.0 |
N/A = not applicable because no predose values were obtained for patients.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Human experience of acute overdose with RESCRIPTOR is limited.
Management of Overdosage:
Treatment of overdosage with RESCRIPTOR (delavirdine mesylate) should consist of general supportive measures, including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdosage with RESCRIPTOR. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Since delavirdine is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
DOSAGE AND ADMINISTRATION
The recommended dosage for RESCRIPTOR (delavirdine mesylate) is 400 mg (four 100-mg tablets)
three times daily administered in combination with other antiretroviral agents. The complete prescribing information for other antiretroviral agents should be consulted for information on dosage and administration.
RESCRIPTOR may be dispersed prior to consumption. To prepare a dispersion, add four tablets to at least 90 mL (3 ounces) of water, allow to stand for a few minutes, and then stir until a uniform dispersion occurs. The dispersion should be consumed promptly. (see PHARMACOLOGY-
Pharmacokinetics, Absorption and Bioavailability). The glass should be rinsed and the rinse swallowed to insure the entire dose is consumed.
RESCRIPTOR may be administered with or without food (see PHARMACOLOGY-
Pharmacokinetics, Absorption and Bioavailability). Patients with achlorhydria should take RESCRIPTOR with an acidic beverage (eg. 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 one hour apart.
PHARMACEUTICAL INFORMATION
I. Drug Substance
Common Name: delavirdine mesylate
Chemical Name: piperazine, 1-[3-[(1-methyl-ethyl)amino]-2-pyridinyl]-4-[[5-
[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-, monomethanesulfonate
Empirical Formula: C22H28N6O3S •CH4O3S
Structural Formula:
N
N
C
N
H
H
S
CH3
O
N
N
NH
CH
CH3
CH3
CH3 S OH
O2
O2
Molecular Weight: 552.68 (free base = 456.57)
Description: Delavirdine mesylate is an odourless white-to-tan crystalline powder. The aqueous solubility of delavirdine free base at 23oC is 2942 µg/mL at pH 1.0, 295 µg/mL at pH 2.0, and 0.81
µg/mL at pH 7.4. The melting point is 211-215oC and pKa is 4.6 at 25oC. A 100 mg/mL solution of delavirdine mesylate in water gives an initial pH of 2.6, before precipitation of free base begins. The measured octanol/water partition coefficient of delavirdine mesylate is pH dependent. At an intermediate range of pH (5 to 9), the partition coefficient (Log [PC]) is 2.98.
II. Composition
Non-medicinal ingredients consist of lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, propylene glycol, titanium dioxide and carnauba wax.
III. Stability and Storage Recommendations
Store at controlled room temperature (15-30ºC). Keep container tightly closed. Protect from high humidity.
AVAILABILITY OF DOSAGE FORMS
Each RESCRIPTOR (delavirdine mesylate) tablet, for oral administration, contains 100 mg of delavirdine mesylate. It is available as 100 mg, white, film-coated, capsule-shaped tablets marked with “U 3761” in HDPE plastic, child resistant bottles with desiccants. Each 750 ml bottle contains
360 tablets.