Rescriptor Information
Rescriptor (Delavirdine mesylate) Description
Rescriptor (Delavirdine mesylate) Tablets contain delavirdine mesylate, a synthetic non-nucleoside reverse transcriptase inhibitor of the human immunodeficiency virus type 1 (HIV-1). The chemical name of delavirdine mesylate is piperazine, 1-[3-[(1-methyl-ethyl)amino]-2-pyridinyl]-4-[[5-[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-, monomethanesulfonate. Its molecular formula is CHNOS • CHOS, and its molecular weight is 552.68. The structural formula is:
Delavirdine mesylate is an odorless white-to-tan crystalline powder. The aqueous solubility of delavirdine free base at 23° C is 2942 µg/mL at pH 1.0, 295 µg/mL at pH 2.0, and 0.81 µg/mL at pH 7.4.
Each Rescriptor (Delavirdine mesylate) Tablet, for oral administration, contains 100 or 200 mg of delavirdine mesylate (henceforth referred to as delavirdine). Inactive ingredients consist of lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, and carnauba wax. In addition, the 100 mg tablet contains Opadry White YS-1-7000-E and the 200 mg tablet contains hypromellose, Opadry White YS-1-18202-A and Pharmaceutical Ink Black.
Rescriptor (Delavirdine mesylate) Clinical Pharmacology
(see also )
Specific drug interaction studies were performed with delavirdine and a number of drugs. Table 1 summarizes the effects of delavirdine on the geometric mean AUC, C and C of coadministered drugs. Table 2 shows the effects of coadministered drugs on the geometric mean AUC, C and C of delavirdine.
For information regarding clinical recommendations, see , and .
Rescriptor (Delavirdine mesylate) Indications And Usage
Rescriptor (Delavirdine mesylate) Tablets are indicated for the treatment of HIV-1 infection in combination with at least 2 other active antiretroviral agents when therapy is warranted.
The following should be considered before initiating therapy with Rescriptor (Delavirdine mesylate) in treatment-naive patients. There are insufficient data directly comparing Rescriptor (Delavirdine mesylate) -containing antiretroviral regimens with currently preferred 3-drug regimens for initial treatment of HIV. In studies comparing regimens consisting of 2 NRTIs (currently considered suboptimal) to Rescriptor (Delavirdine mesylate) plus 2 NRTIs, the proportion of patients receiving the Rescriptor (Delavirdine mesylate) regimen who achieved and sustained an HIV-1 RNA level
Resistant virus emerges rapidly when Rescriptor (Delavirdine mesylate) is administered as monotherapy. Therefore, Rescriptor (Delavirdine mesylate) should always be administered in combination with other antiretroviral agents.
Rescriptor (Delavirdine mesylate) 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 RNA level Study 21 Part II was a double-blind, randomized, placebo-controlled trial comparing treatment with Rescriptor (Delavirdine mesylate) (DLV; 400 mg tid), zidovudine (ZDV; 200 mg tid), and lamivudine (3TC; 150 mg bid) versus Rescriptor (Delavirdine mesylate) (400 mg tid) and zidovudine (200 mg tid) versus zidovudine (200 mg tid) and lamivudine (150 mg bid) 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 CD cell count was 359 cells/mm and mean baseline plasma HIV RNA was 4.4 log copies/mL.
Results showed that the mean increase from baseline in CD count at 52 weeks was 111 cells/mL for Rescriptor (Delavirdine mesylate) + ZDV + 3TC, 27 cells/mL for Rescriptor (Delavirdine mesylate) + ZDV, and 74 cells/mL for ZDV + 3TC.
The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV RNA level
Study 13C was a double-blind, randomized, placebo-controlled trial comparing treatment with Rescriptor (Delavirdine mesylate) (400 mg tid), zidovudine (200 mg tid or 300 bid) and either didanosine (ddI; 200 mg bid), zalcitabine (ddC; 0.75 mg tid) or lamivudine (150 mg bid) versus zidovudine (200 mg tid or 300 mg bid) and either didanosine (200 mg bid), zalcitabine (0.75 mg tid) or lamivudine (150 mg bid) 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 CD cell count was 210 cells/mm and mean baseline plasma HIV RNA was 4.9 log copies/mL.
Results showed that the mean increase from baseline in CD count at 54 weeks was 102 cells/mL for Rescriptor (Delavirdine mesylate) + ZDV + ddI or ddC or 3TC and 56 cells/mL for ZDV + ddI or ddC or 3TC.
The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV RNA level
Results from several smaller supportive studies evaluating the use of Rescriptor (Delavirdine mesylate) 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.
Rescriptor (Delavirdine mesylate) Contraindications
Rescriptor (Delavirdine mesylate) Tablets are contraindicated in patients with known hypersensitivity to any of its ingredients. Coadministration of Rescriptor (Delavirdine mesylate) 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 5.
Rescriptor (Delavirdine mesylate) Warnings
ALERT: Find out about medicines that should NOT be taken with Rescriptor (Delavirdine mesylate) .
Rescriptor (Delavirdine mesylate) Precautions
Severe rash, including rare cases of erythema multiforme and Stevens-Johnson syndrome, has been reported in patients receiving Rescriptor (Delavirdine mesylate) .
In Studies 21 Part II and 13C (see ), rash (including maculopapular rash) was reported in more patients who were treated with Rescriptor (Delavirdine mesylate) 400 mg tid (35% and 32%, respectively) than in those who were not treated with Rescriptor (Delavirdine mesylate) (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 (Delavirdine mesylate) in each study and in none of the patients who were not treated with Rescriptor (Delavirdine mesylate) . Also in Studies 21 Part II and 13C, discontinuations due to rash were reported in more patients who received Rescriptor (Delavirdine mesylate) 400 mg tid (3% and 4%, respectively) than in those who did not receive Rescriptor (Delavirdine mesylate) (0% and 1%, respectively).
In most cases, the duration of the rash was less than two weeks and did not require dose reduction or discontinuation of Rescriptor (Delavirdine mesylate) . Most patients were able to resume therapy after rechallenge with Rescriptor (Delavirdine mesylate) 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 one month is uncommon. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.
A statement to patients and healthcare providers is included on the product's bottle label: A patient package insert (PPI) for Rescriptor (Delavirdine mesylate) is available for patient information.
Patients should be informed that Rescriptor (Delavirdine mesylate) 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 (Delavirdine mesylate) 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 (Delavirdine mesylate) .
Patients should be advised that the use of Rescriptor (Delavirdine mesylate) has not been shown to reduce the risk of transmission of HIV-1.
Patients should be instructed that the major toxicity of Rescriptor (Delavirdine mesylate) is rash and should be advised to promptly notify their physician should rash occur. The majority of rashes associated with Rescriptor (Delavirdine mesylate) occur within 1 to 3 weeks after initiating treatment with Rescriptor (Delavirdine mesylate) . The rash normally resolves in 3 to 14 days and may be treated symptomatically while therapy with Rescriptor (Delavirdine mesylate) 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 (Delavirdine mesylate) every day as prescribed. Patients should not alter the dose of Rescriptor (Delavirdine mesylate) 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 (Delavirdine mesylate) 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 (Delavirdine mesylate) and antacids should be advised to take them at least 1 hour apart.
Because Rescriptor (Delavirdine mesylate) 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 (Delavirdine mesylate) 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.
(see also , , and )
Delavirdine is an inhibitor of CYP3A isoform and other CYP isoforms to a lesser extent including CYP2C9, CYP2D6, and CYP2C19. Coadministration of Rescriptor (Delavirdine mesylate) 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 data suggest that delavirdine may also be metabolized by CYP2D6. Coadministration of Rescriptor (Delavirdine mesylate) and drugs that induce CYP3A, such as rifampin, may decrease delavirdine plasma concentrations and reduce its therapeutic effect. Coadministration of Rescriptor (Delavirdine mesylate) and drugs that inhibit CYP3A may increase delavirdine plasma concentrations.
Delavirdine was negative in a battery of genetic toxicology tests which included an Ames assay, an rat hepatocyte unscheduled DNA synthesis assay, an chromosome aberration assay in human peripheral lymphocytes, an mutation assay in Chinese hamster ovary cells, and an 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.
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
mothers should be instructed not to breastfeed if they are receiving Rescriptor (Delavirdine mesylate) .
Rescriptor (Delavirdine mesylate) Adverse Reactions
The safety of Rescriptor (Delavirdine mesylate) Tablets alone and in combination with other therapies has been studied in approximately 6,000 patients receiving Rescriptor (Delavirdine mesylate) . 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 (Delavirdine mesylate) was skin rash (see and ).
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 (Delavirdine mesylate) 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.
Other adverse events that occurred in patients receiving Rescriptor (Delavirdine mesylate) (in combination treatment) in all phase II and III studies, and considered possibly related to treatment, and of at least ACTG grade 2 in intensity are listed below by body system.
Rescriptor (Delavirdine mesylate) Overdosage
Human experience of acute overdose with Rescriptor (Delavirdine mesylate) is limited.
Rescriptor (Delavirdine mesylate) Dosage And Administration
The recommended dosage for Rescriptor (Delavirdine mesylate) Tablets is 400 mg (four 100 mg or two 200 mg tablets) three times daily. Rescriptor (Delavirdine mesylate) should be used in combination with other antiretroviral therapy. The complete prescribing information for other antiretroviral agents should be consulted for information on dosage and administration.
The 100 mg Rescriptor (Delavirdine mesylate) Tablets may be dispersed in water prior to consumption. To prepare a dispersion, add four 100 mg Rescriptor (Delavirdine mesylate) Tablets to at least 3 ounces of water, allow to stand for a few minutes, and then stir until a uniform dispersion occurs (see ). The dispersion should be consumed promptly. The glass should be rinsed with water and the rinse swallowed to insure the entire dose is consumed. Note: The 200 mg tablets are approximately one-third smaller in size than the 100 mg tablets.
Rescriptor (Delavirdine mesylate) Tablets may be administered with or without food (see ). Patients with achlorhydria should take Rescriptor (Delavirdine mesylate) 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 (Delavirdine mesylate) and antacids should be advised to take them at least one hour apart.
Rescriptor (Delavirdine mesylate) How Supplied
Rescriptor (Delavirdine mesylate) Tablets are available as follows:
100 mg: white, capsule-shaped tablets marked with "U 3761".Bottles of 360 tablets NDC 63010-020-36200 mg: white, capsule-shaped tablets marked with "Rescriptor (Delavirdine mesylate) 200 mg".Bottles of 180 tablets NDC 63010-021-18Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Keep container tightly closed. Protect from high humidity.
Rescriptor (Delavirdine mesylate)
Rescriptor (Delavirdine mesylate) 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 (Delavirdine mesylate) (C 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.
Rescriptor (Delavirdine mesylate)
