U.S. BRAND NAMES — Differin®
PHARMACOLOGIC CATEGORY
Acne Products
Topical Skin Product, Acne
DOSING: ADULTS — Acne: Topical: Apply once daily before bedtime; results appear after 8-12 weeks of therapy.
DOSING: PEDIATRIC — Children >12 years: Refer to adult dosing.
(For additional information see "Adapalene: Pediatric drug information")
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Cream, topical:
Differin®: 0.1% (15 g, 45 g)
Gel, topical:
Differin®: 0.1% (15 g, 45 g) [alcohol free]; 0.3% (45 g) [alcohol free]
DOSAGE FORMS: CONCISE
Cream, topical:
Differin®: 0.1% (15 g, 45 g)
Gel, topical:
Differin®: 0.1% (15 g, 45 g); 0.3% (45 g)
GENERIC EQUIVALENT AVAILABLE — No
USE — Treatment of acne vulgaris
ADVERSE REACTIONS SIGNIFICANT
>10%: Dermatologic: Erythema, scaling, dryness, pruritus, burning, pruritus or burning immediately after application
<1% (Limited to important or life-threatening): Acne flares, conjunctivitis, contact dermatitis, dermatitis, eczema, eyelid edema, skin discoloration, skin irritation, stinging, sunburn, rash (topical cream)
CONTRAINDICATIONS — Hypersensitivity to adapalene or any component in the vehicle gel
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Photosensitivity: Use is associated with increased susceptibility/sensitivity to UV light; avoid sunlamps or excessive sunlight exposure. Daily sunscreen use and other protective measures recommended. Skin irritation: Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning, or pruritus may occur during treatment; these are most likely to occur during the first 2-4 weeks and will usually lessen with continued use.
Disease-related concerns: Eczema: Use with caution in patients with eczema.
Special populations: Pediatrics: Safety and efficacy have not been established in children <12 years of age.
Other warnings/precautions: Appropriate use: For external use only; avoid contact with abraded skin, mucous membranes, eyes, mouth, angles of the nose.
DRUG INTERACTIONS
Vitamin A: May enhance the adverse/toxic effect of Retinoid-like Compounds. Risk D: Consider therapy modification
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — There are no adequate and well-controlled studies in pregnant women. Use only if benefit outweighs the potential risk to fetus.
LACTATION — Excretion in breast milk unknown/use caution
PRICING — (data from drugstore.com)
Cream (Differin)
0.1% (45): $189.50
Gel (Differin)
0.1% (45): $185.59
0.3% (45): $177.06
CANADIAN BRAND NAMES — Differin®; Differin® XP
INTERNATIONAL BRAND NAMES — Aclene (KP); Acure (TW); Adaferin (CR, DO, GT, HN, IN, MX, NI, PA, SV); Adaferin Gel (IL); Beautyface (TW); Butipalen (KP); Deriva (MY); Differin (AR, AU, BR, CL, CN, EE, FI, HK, HN, KP, MY, NO, PE, PH, PL, PY, SG, TH, TW, UY, VE, ZA); Differin Gel (AT, BE, CH, DE, GB, IE, IL, IT, SE); Differine (CZ, ES, FR); Elibel (KP); Evalen (ID); Klenzit (PH); Panalene (AR); Pindome (TW); Redap (DK); Rozac (IN)
MECHANISM OF ACTION — Retinoid-like compound which is a modulator of cellular differentiation, keratinization, and inflammatory processes, all of which represent important features in the pathology of acne vulgaris
PHARMACODYNAMICS / KINETICS
Absorption: Topical: Minimal
Excretion: Bile
PATIENT INFORMATION — Thoroughly wash hands after applying. Avoid hydration of skin immediately before application. Minimize exposure to sunlight. Avoid washing face more frequently than 2-3 times/day. If severe irritation occurs, discontinue medication temporarily and adjust dose when irritation subsides. Avoid using topical preparations with high alcoholic content during treatment period. Do not exceed prescribed dose.
Monday, May 24, 2010
Tuesday, May 18, 2010
Adalimumab
SPECIAL ALERTS
Tumor Necrosis Factor-Alpha Blockers Associated with Malignancies and New-Onset Psoriasis - Updated August 2009
The U.S. Food and Drug Administration (FDA) has completed its previously announced analysis of Tumor Necrosis Factor-Alpha (TNF) blockers, and is alerting healthcare professionals of an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults. Health Canada has recently issued a similar alert to Canadian practitioners. The FDA analysis is an update to the June 2008 Early Communication About an Ongoing Safety Review regarding a possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. In addition, as a result of a separate analysis, the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.
Pediatric malignancies: Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin's and non-Hodgkin's lymphoma). Other malignancies such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate); however, the role of TNF blockers in the development of malignancies in children could not be excluded. Further data regarding the incidence of these malignancies is expected from ongoing postmarketing studies and registries conducted by the TNF blocker manufacturers.
Leukemia: The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients using TNF blockers. Average onset time to development of leukemia was within the first 1-2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF blockers.
New-onset psoriasis: In a separate analysis, the FDA reviewed 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers for the treatment of conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, 2 were reported in children and 12 required hospitalization, the most severe outcome. Improvement was seen when the TNF blocker was discontinued. The FDA concluded that there is a possible association with new-onset psoriasis and the use of TNF blockers.
The FDA has required the manufacturers of TNF blockers to update the Boxed Warnings and the Warnings in the prescribing information as it relates to malignancies, to update the Adverse Events section to include reported cases of new-onset psoriasis, and to revise the medication guide to reflect this information. Health Canada is also working with their respective manufacturers to update the Canadian labeling with this important safety information. Patients should be monitored closely for signs and symptoms suggestive of malignancy or new-onset psoriasis, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.
Additional information can be found at:
U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175843.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_137-eng.php
Tumor Necrosis Factor-Alpha Blockers Associated with Unrecognized Invasive Fungal Infections - Updated May 28, 2009
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of an increased risk for opportunistic fungal infections in patients treated with antitumor necrosis factor (anti-TNF) agents adalimumab (Humira®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), and infliximab (Remicade®). The FDA has received reports of pulmonary and disseminated cases of histoplasmosis, coccidioidomycosis, blastomycosis, and other fungal infections associated with use of these agents. In some cases, the symptoms of fungal infection (eg, fever, cough, malaise, dyspnea, fatigue) were unrecognized and precluded prompt antifungal treatment, resulting in 12 deaths. In response, the FDA is requiring manufacturers of these agents to strengthen the boxed warning statement in the labeling to further emphasize the risk of invasive fungal infection. Patients should be monitored closely for signs and symptoms suggestive of fungal infection, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation. Symptomatic patients should be questioned about their residence in or travel from areas of endemic mycoses, which should prompt consideration of empiric antifungal therapy.
Additional information can be found at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm163195.htm
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm162802.htm
U.S. BRAND NAMES — Humira®
PHARMACOLOGIC CATEGORY
Antirheumatic, Disease Modifying
Gastrointestinal Agent, Miscellaneous
Monoclonal Antibody
Tumor Necrosis Factor (TNF) Blocking Agent
DOSING: ADULTS
Rheumatoid arthritis: SubQ: 40 mg every other week; may be administered with other DMARDs; patients not taking methotrexate may increase dose to 40 mg every week
Ankylosing spondylitis, psoriatic arthritis: SubQ: 40 mg every other week
Crohn's disease: SubQ: Initial: 160 mg given as 4 injections on day 1 or over 2 days, then 80 mg 2 weeks later (day 15); Maintenance: 40 mg every other week beginning day 29
Plaque psoriasis: SubQ: Initial: 80 mg as a single dose; maintenance: 40 mg every other week beginning 1 week after initial dose
DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children ≥ 4 years: SubQ:
15 kg to <30 kg: 20 mg every other week
≥ 30 kg: 40 mg every other week
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL) [contains polysorbate 80]
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]
DOSAGE FORMS: CONCISE
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL)
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — For SubQ injection; rotate injection sites. Do not use if solution is discolored. Do not administer to skin which is red, tender, bruised, or hard; rotate injection sites. Needle cap of the prefilled syringe may contain latex.
USE
Treatment of active rheumatoid arthritis (moderate-to-severe) and active psoriatic arthritis; may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs); treatment of ankylosing spondylitis
Treatment of moderately- to severely-active Crohn's disease in patients with inadequate response to conventional treatment, or patients who have lost response to or are intolerant of infliximab
Treatment of moderate-to-severe plaque psoriasis
Treatment of moderately- to severely-active juvenile idiopathic arthritis
ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Headache (12%)
Dermatologic: Rash (6% to 12%)
Local: Injection site reaction (12% to 20%; includes erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: CPK increased (15%)
Respiratory: Upper respiratory tract infection (17%), sinusitis (11%)
Miscellaneous: Antibodies to adalimumab (3% to 26%; significance unknown), positive ANA (12%)
5% to 10%:
Cardiovascular: Hypertension (5%)
Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%)
Gastrointestinal: Nausea (9%), abdominal pain (7%)
Genitourinary: Urinary tract infection (8%)
Hepatic: Alkaline phosphatase increased (5%)
Local: Injection site reaction (8%; other than erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: Back pain (6%)
Renal: Hematuria (5%)
Miscellaneous: Accidental injury (10%), flu-like syndrome (7%)
<5%:
Cardiovascular: Arrhythmia, atrial fibrillation, chest pain, CHF, coronary artery disorder, heart arrest, MI, palpitation, pericardial effusion, pericarditis, peripheral edema, syncope, tachycardia, thrombosis (leg), vascular disorder
Central nervous system: Confusion, fever, hypertensive encephalopathy, multiple sclerosis, subdural hematoma
Dermatologic: Cellulitis, erysipelas
Endocrine & metabolic: Dehydration, menstrual disorder, parathyroid disorder
Gastrointestinal: Diverticulitis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, vomiting
Genitourinary: Cystitis, pelvic pain
Hematologic: Agranulocytosis, granulocytopenia, leukopenia, pancytopenia, paraproteinemia, polycythemia
Hepatic: Cholecystitis, cholelithiasis, hepatic necrosis
Neuromuscular & skeletal: Arthralgia, arthritis, bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pain in extremity, paresthesia, pyogenic arthritis, synovitis, tendon disorder, tremor
Ocular: Cataract
Renal: Kidney calculus, pyelonephritis
Respiratory: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion, pneumonia
Miscellaneous: Adenoma, allergic reactions (1%), carcinoma (including breast, gastrointestinal, skin, urogenital), healing abnormality, herpes zoster, ketosis, lupus erythematosus syndrome, lymphoma, melanoma, postsurgical infection, sepsis, tuberculosis (reactivation of latent infection; miliary, lymphatic, peritoneal and pulmonary)
Postmarketing and/or case reports: Anaphylactoid reaction, anaphylaxis, angioneurotic edema, aplastic anemia, cutaneous vasculitis, cytopenia, erythema multiforme, fixed drug eruption, Guillain-Barre syndrome, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal perforation, leukemias, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), septic arthritis, thrombocytopenia, transaminases increased, urticaria
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
Canada labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection)
WARNINGS / PRECAUTIONS
Boxed warnings: Fatal infections: . Tuberculosis evaluation: .
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioedema; medications for the treatment of hypersensitivity reactions should be available for immediate use. Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop. Fatal infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (including tuberculosis, invasive fungal and other opportunistic infections) have been reported in patients receiving TNF-blocking agents, including adalimumab. Cases of unrecognized invasive fungal infections (eg, histoplasmosis, blastomycosis, coccidioidomycosis) have also been reported with anti-TNF agent use. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Other opportunistic infections included Aspergillus and Nocardia. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (eg, diabetes or residence/travel from areas of endemic mycoses). Do not give to patients with an active chronic or localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued. Hepatitis B: Rare reactivation of hepatitis B virus (HBV) has occurred in chronic virus carriers; evaluate prior to initiation, during, and for several months after treatment. Evaluate patients at risk for HBV infection prior to therapy to determine HBV status. Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.9/100 patient years), when compared to the control group (0.3/100 patient years). As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. Pancytopenia: Rare cases of pancytopenia (including aplastic anemia) have been reported with TNF-blocking agents; with significant hematologic abnormalities, consider discontinuing therapy. Tuberculosis evaluation: Tuberculosis (disseminated or extrapulmonary) has been reactivated while on adalimumab; most cases have been reported within the first 8 months of treatment. Doses higher than recommended are associated with an increased risk for tuberculosis reactivation. [U.S. Boxed Warnings]: Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment; active tuberculosis has developed in this population during treatment. Use with caution in patients who have resided in regions where tuberculosis is endemic
Disease-related concerns: Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of optic neuritis and demyelinating disease (new onset or exacerbation) have been reported. Heart failure (HF): Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported.
Dosage form specific issues: Latex: The packaging (needle cover of prefilled syringe) may contain latex. Polysorbate 80: Product may contain polysorbate 80.
Other warnings/precautions: Immunizations: Patients should be brought up to date with all immunizations before initiating therapy; live vaccines should not be given concurrently. There is no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.
DRUG INTERACTIONS
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/nutraceutical: Echinacea may decrease the therapeutic effects of adalimumab; avoid concurrent use.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to adalimumab during pregnancy (877-311-8972).
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — It is not known whether adalimumab is secreted in human milk. Because many immunoglobulins are secreted in milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
PRICING — (data from drugstore.com)
Kit (Humira)
40 mg/0.8 mL (2): $1635.66
Kit (Humira Pen)
40 mg/0.8 mL (2): $1663.63
MONITORING PARAMETERS — Place and read PPD before initiation. Monitor improvement of symptoms and physical function assessments; CBC; signs of infection, bleeding or bruising.
CANADIAN BRAND NAMES — Humira®
INTERNATIONAL BRAND NAMES — Humira (AE, AR, AT, AU, BE, BG, BH, BR, CH, CN, CO, CY, CZ, DE, DK, EC, EG, FI, FR, GB, GR, HK, HN, IE, IL, IQ, IR, IT, JO, KP, KW, LB, LY, MX, MY, NL, NO, OM, PE, PT, PY, QA, RU, SA, SE, SG, SY, TR, TW, UY, VE, YE); Trudexa (AT, BE, BG, CH, CZ, DE, DK, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
MECHANISM OF ACTION — Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFalpha receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn's disease; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 4.7-6 L; Synovial fluid concentrations: 31% to 96% of serum
Bioavailability: Absolute: 64%
Half-life elimination: Terminal: ~2 weeks (range 10-20 days)
Time to peak, serum: SubQ: 131 +/- 56 hours
Excretion: Clearance increased in the presence of antiadalimumab antibodies; decreased in patients 40 years and older
PATIENT INFORMATION — May cause headache, nausea, or stomach pain. Notify prescriber of any signs of infection.
Tumor Necrosis Factor-Alpha Blockers Associated with Malignancies and New-Onset Psoriasis - Updated August 2009
The U.S. Food and Drug Administration (FDA) has completed its previously announced analysis of Tumor Necrosis Factor-Alpha (TNF) blockers, and is alerting healthcare professionals of an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults. Health Canada has recently issued a similar alert to Canadian practitioners. The FDA analysis is an update to the June 2008 Early Communication About an Ongoing Safety Review regarding a possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. In addition, as a result of a separate analysis, the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.
Pediatric malignancies: Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin's and non-Hodgkin's lymphoma). Other malignancies such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate); however, the role of TNF blockers in the development of malignancies in children could not be excluded. Further data regarding the incidence of these malignancies is expected from ongoing postmarketing studies and registries conducted by the TNF blocker manufacturers.
Leukemia: The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients using TNF blockers. Average onset time to development of leukemia was within the first 1-2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF blockers.
New-onset psoriasis: In a separate analysis, the FDA reviewed 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers for the treatment of conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, 2 were reported in children and 12 required hospitalization, the most severe outcome. Improvement was seen when the TNF blocker was discontinued. The FDA concluded that there is a possible association with new-onset psoriasis and the use of TNF blockers.
The FDA has required the manufacturers of TNF blockers to update the Boxed Warnings and the Warnings in the prescribing information as it relates to malignancies, to update the Adverse Events section to include reported cases of new-onset psoriasis, and to revise the medication guide to reflect this information. Health Canada is also working with their respective manufacturers to update the Canadian labeling with this important safety information. Patients should be monitored closely for signs and symptoms suggestive of malignancy or new-onset psoriasis, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.
Additional information can be found at:
U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175843.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_137-eng.php
Tumor Necrosis Factor-Alpha Blockers Associated with Unrecognized Invasive Fungal Infections - Updated May 28, 2009
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of an increased risk for opportunistic fungal infections in patients treated with antitumor necrosis factor (anti-TNF) agents adalimumab (Humira®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), and infliximab (Remicade®). The FDA has received reports of pulmonary and disseminated cases of histoplasmosis, coccidioidomycosis, blastomycosis, and other fungal infections associated with use of these agents. In some cases, the symptoms of fungal infection (eg, fever, cough, malaise, dyspnea, fatigue) were unrecognized and precluded prompt antifungal treatment, resulting in 12 deaths. In response, the FDA is requiring manufacturers of these agents to strengthen the boxed warning statement in the labeling to further emphasize the risk of invasive fungal infection. Patients should be monitored closely for signs and symptoms suggestive of fungal infection, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation. Symptomatic patients should be questioned about their residence in or travel from areas of endemic mycoses, which should prompt consideration of empiric antifungal therapy.
Additional information can be found at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm163195.htm
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm162802.htm
U.S. BRAND NAMES — Humira®
PHARMACOLOGIC CATEGORY
Antirheumatic, Disease Modifying
Gastrointestinal Agent, Miscellaneous
Monoclonal Antibody
Tumor Necrosis Factor (TNF) Blocking Agent
DOSING: ADULTS
Rheumatoid arthritis: SubQ: 40 mg every other week; may be administered with other DMARDs; patients not taking methotrexate may increase dose to 40 mg every week
Ankylosing spondylitis, psoriatic arthritis: SubQ: 40 mg every other week
Crohn's disease: SubQ: Initial: 160 mg given as 4 injections on day 1 or over 2 days, then 80 mg 2 weeks later (day 15); Maintenance: 40 mg every other week beginning day 29
Plaque psoriasis: SubQ: Initial: 80 mg as a single dose; maintenance: 40 mg every other week beginning 1 week after initial dose
DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children ≥ 4 years: SubQ:
15 kg to <30 kg: 20 mg every other week
≥ 30 kg: 40 mg every other week
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL) [contains polysorbate 80]
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]
DOSAGE FORMS: CONCISE
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL)
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — For SubQ injection; rotate injection sites. Do not use if solution is discolored. Do not administer to skin which is red, tender, bruised, or hard; rotate injection sites. Needle cap of the prefilled syringe may contain latex.
USE
Treatment of active rheumatoid arthritis (moderate-to-severe) and active psoriatic arthritis; may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs); treatment of ankylosing spondylitis
Treatment of moderately- to severely-active Crohn's disease in patients with inadequate response to conventional treatment, or patients who have lost response to or are intolerant of infliximab
Treatment of moderate-to-severe plaque psoriasis
Treatment of moderately- to severely-active juvenile idiopathic arthritis
ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Headache (12%)
Dermatologic: Rash (6% to 12%)
Local: Injection site reaction (12% to 20%; includes erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: CPK increased (15%)
Respiratory: Upper respiratory tract infection (17%), sinusitis (11%)
Miscellaneous: Antibodies to adalimumab (3% to 26%; significance unknown), positive ANA (12%)
5% to 10%:
Cardiovascular: Hypertension (5%)
Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%)
Gastrointestinal: Nausea (9%), abdominal pain (7%)
Genitourinary: Urinary tract infection (8%)
Hepatic: Alkaline phosphatase increased (5%)
Local: Injection site reaction (8%; other than erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: Back pain (6%)
Renal: Hematuria (5%)
Miscellaneous: Accidental injury (10%), flu-like syndrome (7%)
<5%:
Cardiovascular: Arrhythmia, atrial fibrillation, chest pain, CHF, coronary artery disorder, heart arrest, MI, palpitation, pericardial effusion, pericarditis, peripheral edema, syncope, tachycardia, thrombosis (leg), vascular disorder
Central nervous system: Confusion, fever, hypertensive encephalopathy, multiple sclerosis, subdural hematoma
Dermatologic: Cellulitis, erysipelas
Endocrine & metabolic: Dehydration, menstrual disorder, parathyroid disorder
Gastrointestinal: Diverticulitis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, vomiting
Genitourinary: Cystitis, pelvic pain
Hematologic: Agranulocytosis, granulocytopenia, leukopenia, pancytopenia, paraproteinemia, polycythemia
Hepatic: Cholecystitis, cholelithiasis, hepatic necrosis
Neuromuscular & skeletal: Arthralgia, arthritis, bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pain in extremity, paresthesia, pyogenic arthritis, synovitis, tendon disorder, tremor
Ocular: Cataract
Renal: Kidney calculus, pyelonephritis
Respiratory: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion, pneumonia
Miscellaneous: Adenoma, allergic reactions (1%), carcinoma (including breast, gastrointestinal, skin, urogenital), healing abnormality, herpes zoster, ketosis, lupus erythematosus syndrome, lymphoma, melanoma, postsurgical infection, sepsis, tuberculosis (reactivation of latent infection; miliary, lymphatic, peritoneal and pulmonary)
Postmarketing and/or case reports: Anaphylactoid reaction, anaphylaxis, angioneurotic edema, aplastic anemia, cutaneous vasculitis, cytopenia, erythema multiforme, fixed drug eruption, Guillain-Barre syndrome, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal perforation, leukemias, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), septic arthritis, thrombocytopenia, transaminases increased, urticaria
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
Canada labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection)
WARNINGS / PRECAUTIONS
Boxed warnings: Fatal infections: . Tuberculosis evaluation: .
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioedema; medications for the treatment of hypersensitivity reactions should be available for immediate use. Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop. Fatal infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (including tuberculosis, invasive fungal and other opportunistic infections) have been reported in patients receiving TNF-blocking agents, including adalimumab. Cases of unrecognized invasive fungal infections (eg, histoplasmosis, blastomycosis, coccidioidomycosis) have also been reported with anti-TNF agent use. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Other opportunistic infections included Aspergillus and Nocardia. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (eg, diabetes or residence/travel from areas of endemic mycoses). Do not give to patients with an active chronic or localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued. Hepatitis B: Rare reactivation of hepatitis B virus (HBV) has occurred in chronic virus carriers; evaluate prior to initiation, during, and for several months after treatment. Evaluate patients at risk for HBV infection prior to therapy to determine HBV status. Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.9/100 patient years), when compared to the control group (0.3/100 patient years). As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. Pancytopenia: Rare cases of pancytopenia (including aplastic anemia) have been reported with TNF-blocking agents; with significant hematologic abnormalities, consider discontinuing therapy. Tuberculosis evaluation: Tuberculosis (disseminated or extrapulmonary) has been reactivated while on adalimumab; most cases have been reported within the first 8 months of treatment. Doses higher than recommended are associated with an increased risk for tuberculosis reactivation. [U.S. Boxed Warnings]: Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment; active tuberculosis has developed in this population during treatment. Use with caution in patients who have resided in regions where tuberculosis is endemic
Disease-related concerns: Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of optic neuritis and demyelinating disease (new onset or exacerbation) have been reported. Heart failure (HF): Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported.
Dosage form specific issues: Latex: The packaging (needle cover of prefilled syringe) may contain latex. Polysorbate 80: Product may contain polysorbate 80.
Other warnings/precautions: Immunizations: Patients should be brought up to date with all immunizations before initiating therapy; live vaccines should not be given concurrently. There is no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.
DRUG INTERACTIONS
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/nutraceutical: Echinacea may decrease the therapeutic effects of adalimumab; avoid concurrent use.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to adalimumab during pregnancy (877-311-8972).
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — It is not known whether adalimumab is secreted in human milk. Because many immunoglobulins are secreted in milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
PRICING — (data from drugstore.com)
Kit (Humira)
40 mg/0.8 mL (2): $1635.66
Kit (Humira Pen)
40 mg/0.8 mL (2): $1663.63
MONITORING PARAMETERS — Place and read PPD before initiation. Monitor improvement of symptoms and physical function assessments; CBC; signs of infection, bleeding or bruising.
CANADIAN BRAND NAMES — Humira®
INTERNATIONAL BRAND NAMES — Humira (AE, AR, AT, AU, BE, BG, BH, BR, CH, CN, CO, CY, CZ, DE, DK, EC, EG, FI, FR, GB, GR, HK, HN, IE, IL, IQ, IR, IT, JO, KP, KW, LB, LY, MX, MY, NL, NO, OM, PE, PT, PY, QA, RU, SA, SE, SG, SY, TR, TW, UY, VE, YE); Trudexa (AT, BE, BG, CH, CZ, DE, DK, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
MECHANISM OF ACTION — Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFalpha receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn's disease; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 4.7-6 L; Synovial fluid concentrations: 31% to 96% of serum
Bioavailability: Absolute: 64%
Half-life elimination: Terminal: ~2 weeks (range 10-20 days)
Time to peak, serum: SubQ: 131 +/- 56 hours
Excretion: Clearance increased in the presence of antiadalimumab antibodies; decreased in patients 40 years and older
PATIENT INFORMATION — May cause headache, nausea, or stomach pain. Notify prescriber of any signs of infection.
Adalimumab
SPECIAL ALERTS
Tumor Necrosis Factor-Alpha Blockers Associated with Malignancies and New-Onset Psoriasis - Updated August 2009
The U.S. Food and Drug Administration (FDA) has completed its previously announced analysis of Tumor Necrosis Factor-Alpha (TNF) blockers, and is alerting healthcare professionals of an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults. Health Canada has recently issued a similar alert to Canadian practitioners. The FDA analysis is an update to the June 2008 Early Communication About an Ongoing Safety Review regarding a possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. In addition, as a result of a separate analysis, the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.
Pediatric malignancies: Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin's and non-Hodgkin's lymphoma). Other malignancies such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate); however, the role of TNF blockers in the development of malignancies in children could not be excluded. Further data regarding the incidence of these malignancies is expected from ongoing postmarketing studies and registries conducted by the TNF blocker manufacturers.
Leukemia: The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients using TNF blockers. Average onset time to development of leukemia was within the first 1-2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF blockers.
New-onset psoriasis: In a separate analysis, the FDA reviewed 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers for the treatment of conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, 2 were reported in children and 12 required hospitalization, the most severe outcome. Improvement was seen when the TNF blocker was discontinued. The FDA concluded that there is a possible association with new-onset psoriasis and the use of TNF blockers.
The FDA has required the manufacturers of TNF blockers to update the Boxed Warnings and the Warnings in the prescribing information as it relates to malignancies, to update the Adverse Events section to include reported cases of new-onset psoriasis, and to revise the medication guide to reflect this information. Health Canada is also working with their respective manufacturers to update the Canadian labeling with this important safety information. Patients should be monitored closely for signs and symptoms suggestive of malignancy or new-onset psoriasis, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.
Additional information can be found at:
U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175843.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_137-eng.php
Tumor Necrosis Factor-Alpha Blockers Associated with Unrecognized Invasive Fungal Infections - Updated May 28, 2009
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of an increased risk for opportunistic fungal infections in patients treated with antitumor necrosis factor (anti-TNF) agents adalimumab (Humira®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), and infliximab (Remicade®). The FDA has received reports of pulmonary and disseminated cases of histoplasmosis, coccidioidomycosis, blastomycosis, and other fungal infections associated with use of these agents. In some cases, the symptoms of fungal infection (eg, fever, cough, malaise, dyspnea, fatigue) were unrecognized and precluded prompt antifungal treatment, resulting in 12 deaths. In response, the FDA is requiring manufacturers of these agents to strengthen the boxed warning statement in the labeling to further emphasize the risk of invasive fungal infection. Patients should be monitored closely for signs and symptoms suggestive of fungal infection, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation. Symptomatic patients should be questioned about their residence in or travel from areas of endemic mycoses, which should prompt consideration of empiric antifungal therapy.
Additional information can be found at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm163195.htm
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm162802.htm
U.S. BRAND NAMES — Humira®
PHARMACOLOGIC CATEGORY
Antirheumatic, Disease Modifying
Gastrointestinal Agent, Miscellaneous
Monoclonal Antibody
Tumor Necrosis Factor (TNF) Blocking Agent
DOSING: ADULTS
Rheumatoid arthritis: SubQ: 40 mg every other week; may be administered with other DMARDs; patients not taking methotrexate may increase dose to 40 mg every week
Ankylosing spondylitis, psoriatic arthritis: SubQ: 40 mg every other week
Crohn's disease: SubQ: Initial: 160 mg given as 4 injections on day 1 or over 2 days, then 80 mg 2 weeks later (day 15); Maintenance: 40 mg every other week beginning day 29
Plaque psoriasis: SubQ: Initial: 80 mg as a single dose; maintenance: 40 mg every other week beginning 1 week after initial dose
DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children ≥ 4 years: SubQ:
15 kg to <30 kg: 20 mg every other week
≥ 30 kg: 40 mg every other week
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL) [contains polysorbate 80]
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]
DOSAGE FORMS: CONCISE
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL)
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — For SubQ injection; rotate injection sites. Do not use if solution is discolored. Do not administer to skin which is red, tender, bruised, or hard; rotate injection sites. Needle cap of the prefilled syringe may contain latex.
USE
Treatment of active rheumatoid arthritis (moderate-to-severe) and active psoriatic arthritis; may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs); treatment of ankylosing spondylitis
Treatment of moderately- to severely-active Crohn's disease in patients with inadequate response to conventional treatment, or patients who have lost response to or are intolerant of infliximab
Treatment of moderate-to-severe plaque psoriasis
Treatment of moderately- to severely-active juvenile idiopathic arthritis
ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Headache (12%)
Dermatologic: Rash (6% to 12%)
Local: Injection site reaction (12% to 20%; includes erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: CPK increased (15%)
Respiratory: Upper respiratory tract infection (17%), sinusitis (11%)
Miscellaneous: Antibodies to adalimumab (3% to 26%; significance unknown), positive ANA (12%)
5% to 10%:
Cardiovascular: Hypertension (5%)
Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%)
Gastrointestinal: Nausea (9%), abdominal pain (7%)
Genitourinary: Urinary tract infection (8%)
Hepatic: Alkaline phosphatase increased (5%)
Local: Injection site reaction (8%; other than erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: Back pain (6%)
Renal: Hematuria (5%)
Miscellaneous: Accidental injury (10%), flu-like syndrome (7%)
<5%:
Cardiovascular: Arrhythmia, atrial fibrillation, chest pain, CHF, coronary artery disorder, heart arrest, MI, palpitation, pericardial effusion, pericarditis, peripheral edema, syncope, tachycardia, thrombosis (leg), vascular disorder
Central nervous system: Confusion, fever, hypertensive encephalopathy, multiple sclerosis, subdural hematoma
Dermatologic: Cellulitis, erysipelas
Endocrine & metabolic: Dehydration, menstrual disorder, parathyroid disorder
Gastrointestinal: Diverticulitis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, vomiting
Genitourinary: Cystitis, pelvic pain
Hematologic: Agranulocytosis, granulocytopenia, leukopenia, pancytopenia, paraproteinemia, polycythemia
Hepatic: Cholecystitis, cholelithiasis, hepatic necrosis
Neuromuscular & skeletal: Arthralgia, arthritis, bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pain in extremity, paresthesia, pyogenic arthritis, synovitis, tendon disorder, tremor
Ocular: Cataract
Renal: Kidney calculus, pyelonephritis
Respiratory: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion, pneumonia
Miscellaneous: Adenoma, allergic reactions (1%), carcinoma (including breast, gastrointestinal, skin, urogenital), healing abnormality, herpes zoster, ketosis, lupus erythematosus syndrome, lymphoma, melanoma, postsurgical infection, sepsis, tuberculosis (reactivation of latent infection; miliary, lymphatic, peritoneal and pulmonary)
Postmarketing and/or case reports: Anaphylactoid reaction, anaphylaxis, angioneurotic edema, aplastic anemia, cutaneous vasculitis, cytopenia, erythema multiforme, fixed drug eruption, Guillain-Barre syndrome, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal perforation, leukemias, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), septic arthritis, thrombocytopenia, transaminases increased, urticaria
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
Canada labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection)
WARNINGS / PRECAUTIONS
Boxed warnings: Fatal infections: . Tuberculosis evaluation: .
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioedema; medications for the treatment of hypersensitivity reactions should be available for immediate use. Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop. Fatal infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (including tuberculosis, invasive fungal and other opportunistic infections) have been reported in patients receiving TNF-blocking agents, including adalimumab. Cases of unrecognized invasive fungal infections (eg, histoplasmosis, blastomycosis, coccidioidomycosis) have also been reported with anti-TNF agent use. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Other opportunistic infections included Aspergillus and Nocardia. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (eg, diabetes or residence/travel from areas of endemic mycoses). Do not give to patients with an active chronic or localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued. Hepatitis B: Rare reactivation of hepatitis B virus (HBV) has occurred in chronic virus carriers; evaluate prior to initiation, during, and for several months after treatment. Evaluate patients at risk for HBV infection prior to therapy to determine HBV status. Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.9/100 patient years), when compared to the control group (0.3/100 patient years). As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. Pancytopenia: Rare cases of pancytopenia (including aplastic anemia) have been reported with TNF-blocking agents; with significant hematologic abnormalities, consider discontinuing therapy. Tuberculosis evaluation: Tuberculosis (disseminated or extrapulmonary) has been reactivated while on adalimumab; most cases have been reported within the first 8 months of treatment. Doses higher than recommended are associated with an increased risk for tuberculosis reactivation. [U.S. Boxed Warnings]: Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment; active tuberculosis has developed in this population during treatment. Use with caution in patients who have resided in regions where tuberculosis is endemic
Disease-related concerns: Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of optic neuritis and demyelinating disease (new onset or exacerbation) have been reported. Heart failure (HF): Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported.
Dosage form specific issues: Latex: The packaging (needle cover of prefilled syringe) may contain latex. Polysorbate 80: Product may contain polysorbate 80.
Other warnings/precautions: Immunizations: Patients should be brought up to date with all immunizations before initiating therapy; live vaccines should not be given concurrently. There is no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.
DRUG INTERACTIONS
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/nutraceutical: Echinacea may decrease the therapeutic effects of adalimumab; avoid concurrent use.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to adalimumab during pregnancy (877-311-8972).
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — It is not known whether adalimumab is secreted in human milk. Because many immunoglobulins are secreted in milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
PRICING — (data from drugstore.com)
Kit (Humira)
40 mg/0.8 mL (2): $1635.66
Kit (Humira Pen)
40 mg/0.8 mL (2): $1663.63
MONITORING PARAMETERS — Place and read PPD before initiation. Monitor improvement of symptoms and physical function assessments; CBC; signs of infection, bleeding or bruising.
CANADIAN BRAND NAMES — Humira®
INTERNATIONAL BRAND NAMES — Humira (AE, AR, AT, AU, BE, BG, BH, BR, CH, CN, CO, CY, CZ, DE, DK, EC, EG, FI, FR, GB, GR, HK, HN, IE, IL, IQ, IR, IT, JO, KP, KW, LB, LY, MX, MY, NL, NO, OM, PE, PT, PY, QA, RU, SA, SE, SG, SY, TR, TW, UY, VE, YE); Trudexa (AT, BE, BG, CH, CZ, DE, DK, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
MECHANISM OF ACTION — Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFalpha receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn's disease; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 4.7-6 L; Synovial fluid concentrations: 31% to 96% of serum
Bioavailability: Absolute: 64%
Half-life elimination: Terminal: ~2 weeks (range 10-20 days)
Time to peak, serum: SubQ: 131 +/- 56 hours
Excretion: Clearance increased in the presence of antiadalimumab antibodies; decreased in patients 40 years and older
PATIENT INFORMATION — May cause headache, nausea, or stomach pain. Notify prescriber of any signs of infection.
Tumor Necrosis Factor-Alpha Blockers Associated with Malignancies and New-Onset Psoriasis - Updated August 2009
The U.S. Food and Drug Administration (FDA) has completed its previously announced analysis of Tumor Necrosis Factor-Alpha (TNF) blockers, and is alerting healthcare professionals of an increased risk of lymphomas in children and adolescents and leukemia in all patients, including adults. Health Canada has recently issued a similar alert to Canadian practitioners. The FDA analysis is an update to the June 2008 Early Communication About an Ongoing Safety Review regarding a possible association between the use of TNF blockers and the development of lymphoma and other cancers in children and young adults. In addition, as a result of a separate analysis, the FDA is also notifying healthcare professionals of an increased risk of new-onset psoriasis in all patients, including adults.
Pediatric malignancies: Forty-eight cases of malignancy were identified by the FDA in children and adolescents with the use of TNF blockers. Etanercept and infliximab were the only TNF blockers included in the analysis. Of the 48 cases, ~50% were lymphomas (eg, Hodgkin's and non-Hodgkin's lymphoma). Other malignancies such as leukemia, melanoma, and solid organ tumors were reported; malignancies rarely seen in children (eg, leiomyosarcoma, hepatic malignancies, and renal cell carcinoma) were also observed. Of note, most of these cases (88%) were receiving other immunosuppressive medications (eg, azathioprine and methotrexate); however, the role of TNF blockers in the development of malignancies in children could not be excluded. Further data regarding the incidence of these malignancies is expected from ongoing postmarketing studies and registries conducted by the TNF blocker manufacturers.
Leukemia: The FDA also reviewed 147 postmarketing reports of leukemia (including acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) in patients using TNF blockers. Average onset time to development of leukemia was within the first 1-2 years of TNF blocker initiation. Although most patients were receiving other immunosuppressive agents, the role of TNF blockers in the development of leukemia could not be excluded. The FDA concluded that there is a possible association with the development of leukemia and the use of TNF blockers.
New-onset psoriasis: In a separate analysis, the FDA reviewed 69 cases of new-onset psoriasis (including pustular, palmoplantar) occurring in patients using TNF blockers for the treatment of conditions other than psoriasis and psoriatic arthritis. Of the 69 cases, 2 were reported in children and 12 required hospitalization, the most severe outcome. Improvement was seen when the TNF blocker was discontinued. The FDA concluded that there is a possible association with new-onset psoriasis and the use of TNF blockers.
The FDA has required the manufacturers of TNF blockers to update the Boxed Warnings and the Warnings in the prescribing information as it relates to malignancies, to update the Adverse Events section to include reported cases of new-onset psoriasis, and to revise the medication guide to reflect this information. Health Canada is also working with their respective manufacturers to update the Canadian labeling with this important safety information. Patients should be monitored closely for signs and symptoms suggestive of malignancy or new-onset psoriasis, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation.
Additional information can be found at:
U.S.: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175843.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_137-eng.php
Tumor Necrosis Factor-Alpha Blockers Associated with Unrecognized Invasive Fungal Infections - Updated May 28, 2009
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of an increased risk for opportunistic fungal infections in patients treated with antitumor necrosis factor (anti-TNF) agents adalimumab (Humira®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), and infliximab (Remicade®). The FDA has received reports of pulmonary and disseminated cases of histoplasmosis, coccidioidomycosis, blastomycosis, and other fungal infections associated with use of these agents. In some cases, the symptoms of fungal infection (eg, fever, cough, malaise, dyspnea, fatigue) were unrecognized and precluded prompt antifungal treatment, resulting in 12 deaths. In response, the FDA is requiring manufacturers of these agents to strengthen the boxed warning statement in the labeling to further emphasize the risk of invasive fungal infection. Patients should be monitored closely for signs and symptoms suggestive of fungal infection, evidence of which should result in prompt discontinuation of the medication and appropriate diagnostic evaluation. Symptomatic patients should be questioned about their residence in or travel from areas of endemic mycoses, which should prompt consideration of empiric antifungal therapy.
Additional information can be found at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm163195.htm
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm162802.htm
U.S. BRAND NAMES — Humira®
PHARMACOLOGIC CATEGORY
Antirheumatic, Disease Modifying
Gastrointestinal Agent, Miscellaneous
Monoclonal Antibody
Tumor Necrosis Factor (TNF) Blocking Agent
DOSING: ADULTS
Rheumatoid arthritis: SubQ: 40 mg every other week; may be administered with other DMARDs; patients not taking methotrexate may increase dose to 40 mg every week
Ankylosing spondylitis, psoriatic arthritis: SubQ: 40 mg every other week
Crohn's disease: SubQ: Initial: 160 mg given as 4 injections on day 1 or over 2 days, then 80 mg 2 weeks later (day 15); Maintenance: 40 mg every other week beginning day 29
Plaque psoriasis: SubQ: Initial: 80 mg as a single dose; maintenance: 40 mg every other week beginning 1 week after initial dose
DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children ≥ 4 years: SubQ:
15 kg to <30 kg: 20 mg every other week
≥ 30 kg: 40 mg every other week
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL) [contains polysorbate 80]
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL) [contains polysorbate 80]
DOSAGE FORMS: CONCISE
Injection, solution [pediatric; preservative free]:
Humira®: 20 mg/0.4 mL (0.4 mL)
Injection, solution [preservative free]:
Humira®: 40 mg/0.8 mL (0.8 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — For SubQ injection; rotate injection sites. Do not use if solution is discolored. Do not administer to skin which is red, tender, bruised, or hard; rotate injection sites. Needle cap of the prefilled syringe may contain latex.
USE
Treatment of active rheumatoid arthritis (moderate-to-severe) and active psoriatic arthritis; may be used alone or in combination with disease-modifying antirheumatic drugs (DMARDs); treatment of ankylosing spondylitis
Treatment of moderately- to severely-active Crohn's disease in patients with inadequate response to conventional treatment, or patients who have lost response to or are intolerant of infliximab
Treatment of moderate-to-severe plaque psoriasis
Treatment of moderately- to severely-active juvenile idiopathic arthritis
ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Headache (12%)
Dermatologic: Rash (6% to 12%)
Local: Injection site reaction (12% to 20%; includes erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: CPK increased (15%)
Respiratory: Upper respiratory tract infection (17%), sinusitis (11%)
Miscellaneous: Antibodies to adalimumab (3% to 26%; significance unknown), positive ANA (12%)
5% to 10%:
Cardiovascular: Hypertension (5%)
Endocrine & metabolic: Hyperlipidemia (7%), hypercholesterolemia (6%)
Gastrointestinal: Nausea (9%), abdominal pain (7%)
Genitourinary: Urinary tract infection (8%)
Hepatic: Alkaline phosphatase increased (5%)
Local: Injection site reaction (8%; other than erythema, itching, hemorrhage, pain, swelling)
Neuromuscular & skeletal: Back pain (6%)
Renal: Hematuria (5%)
Miscellaneous: Accidental injury (10%), flu-like syndrome (7%)
<5%:
Cardiovascular: Arrhythmia, atrial fibrillation, chest pain, CHF, coronary artery disorder, heart arrest, MI, palpitation, pericardial effusion, pericarditis, peripheral edema, syncope, tachycardia, thrombosis (leg), vascular disorder
Central nervous system: Confusion, fever, hypertensive encephalopathy, multiple sclerosis, subdural hematoma
Dermatologic: Cellulitis, erysipelas
Endocrine & metabolic: Dehydration, menstrual disorder, parathyroid disorder
Gastrointestinal: Diverticulitis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, vomiting
Genitourinary: Cystitis, pelvic pain
Hematologic: Agranulocytosis, granulocytopenia, leukopenia, pancytopenia, paraproteinemia, polycythemia
Hepatic: Cholecystitis, cholelithiasis, hepatic necrosis
Neuromuscular & skeletal: Arthralgia, arthritis, bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pain in extremity, paresthesia, pyogenic arthritis, synovitis, tendon disorder, tremor
Ocular: Cataract
Renal: Kidney calculus, pyelonephritis
Respiratory: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion, pneumonia
Miscellaneous: Adenoma, allergic reactions (1%), carcinoma (including breast, gastrointestinal, skin, urogenital), healing abnormality, herpes zoster, ketosis, lupus erythematosus syndrome, lymphoma, melanoma, postsurgical infection, sepsis, tuberculosis (reactivation of latent infection; miliary, lymphatic, peritoneal and pulmonary)
Postmarketing and/or case reports: Anaphylactoid reaction, anaphylaxis, angioneurotic edema, aplastic anemia, cutaneous vasculitis, cytopenia, erythema multiforme, fixed drug eruption, Guillain-Barre syndrome, infections (bacterial, viral, fungal and protozoal), interstitial lung disease (eg, pulmonary fibrosis), intestinal perforation, leukemias, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), septic arthritis, thrombocytopenia, transaminases increased, urticaria
CONTRAINDICATIONS — There are no contraindications listed within the FDA-approved labeling.
Canada labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection)
WARNINGS / PRECAUTIONS
Boxed warnings: Fatal infections: . Tuberculosis evaluation: .
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: May rarely cause hypersensitivity, anaphylaxis, anaphylactoid reactions, or angioedema; medications for the treatment of hypersensitivity reactions should be available for immediate use. Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop. Fatal infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (including tuberculosis, invasive fungal and other opportunistic infections) have been reported in patients receiving TNF-blocking agents, including adalimumab. Cases of unrecognized invasive fungal infections (eg, histoplasmosis, blastomycosis, coccidioidomycosis) have also been reported with anti-TNF agent use. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Other opportunistic infections included Aspergillus and Nocardia. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (eg, diabetes or residence/travel from areas of endemic mycoses). Do not give to patients with an active chronic or localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued. Hepatitis B: Rare reactivation of hepatitis B virus (HBV) has occurred in chronic virus carriers; evaluate prior to initiation, during, and for several months after treatment. Evaluate patients at risk for HBV infection prior to therapy to determine HBV status. Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. A higher incidence of nonmelanoma skin cancers was noted in adalimumab-treated patients (0.9/100 patient years), when compared to the control group (0.3/100 patient years). As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma. Pancytopenia: Rare cases of pancytopenia (including aplastic anemia) have been reported with TNF-blocking agents; with significant hematologic abnormalities, consider discontinuing therapy. Tuberculosis evaluation: Tuberculosis (disseminated or extrapulmonary) has been reactivated while on adalimumab; most cases have been reported within the first 8 months of treatment. Doses higher than recommended are associated with an increased risk for tuberculosis reactivation. [U.S. Boxed Warnings]: Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment; active tuberculosis has developed in this population during treatment. Use with caution in patients who have resided in regions where tuberculosis is endemic
Disease-related concerns: Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of optic neuritis and demyelinating disease (new onset or exacerbation) have been reported. Heart failure (HF): Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported.
Dosage form specific issues: Latex: The packaging (needle cover of prefilled syringe) may contain latex. Polysorbate 80: Product may contain polysorbate 80.
Other warnings/precautions: Immunizations: Patients should be brought up to date with all immunizations before initiating therapy; live vaccines should not be given concurrently. There is no data available concerning the effects of therapy on vaccination or secondary transmission of live vaccines in patients receiving therapy.
DRUG INTERACTIONS
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/nutraceutical: Echinacea may decrease the therapeutic effects of adalimumab; avoid concurrent use.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to adalimumab during pregnancy (877-311-8972).
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — It is not known whether adalimumab is secreted in human milk. Because many immunoglobulins are secreted in milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
PRICING — (data from drugstore.com)
Kit (Humira)
40 mg/0.8 mL (2): $1635.66
Kit (Humira Pen)
40 mg/0.8 mL (2): $1663.63
MONITORING PARAMETERS — Place and read PPD before initiation. Monitor improvement of symptoms and physical function assessments; CBC; signs of infection, bleeding or bruising.
CANADIAN BRAND NAMES — Humira®
INTERNATIONAL BRAND NAMES — Humira (AE, AR, AT, AU, BE, BG, BH, BR, CH, CN, CO, CY, CZ, DE, DK, EC, EG, FI, FR, GB, GR, HK, HN, IE, IL, IQ, IR, IT, JO, KP, KW, LB, LY, MX, MY, NL, NO, OM, PE, PT, PY, QA, RU, SA, SE, SG, SY, TR, TW, UY, VE, YE); Trudexa (AT, BE, BG, CH, CZ, DE, DK, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)
MECHANISM OF ACTION — Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFalpha receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn's disease; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.
PHARMACODYNAMICS / KINETICS
Distribution: Vd: 4.7-6 L; Synovial fluid concentrations: 31% to 96% of serum
Bioavailability: Absolute: 64%
Half-life elimination: Terminal: ~2 weeks (range 10-20 days)
Time to peak, serum: SubQ: 131 +/- 56 hours
Excretion: Clearance increased in the presence of antiadalimumab antibodies; decreased in patients 40 years and older
PATIENT INFORMATION — May cause headache, nausea, or stomach pain. Notify prescriber of any signs of infection.
Acyclovir
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Acyclovir may be confused with ganciclovir, Retrovir®, valACYclovir
Zovirax® may be confused with Valtrex®, Zithromax®, Zostrix®, Zyloprim®, Zyvox®
International issues:
Opthavir® [Mexico] may be confused with Optivar® which is a brand name for azelastine in the U.S.
U.S. BRAND NAMES — Zovirax®
PHARMACOLOGIC CATEGORY
Antiviral Agent
Antiviral Agent, Topical
DOSING: ADULTS — Note: Obese patients should be dosed using ideal body weight
Genital HSV:
I.V.: Immunocompetent: Initial episode, severe: 5 mg/kg/dose every 8 hours for 5-7 days
Oral:
Initial episode: 200 mg every 4 hours while awake (5 times/day) for 10 days (per manufacturer's labeling); 400 mg 3 times/day for 5-10 days has also been reported
Recurrence: 200 mg every 4 hours while awake (5 times/day) for 5 days (per manufacturer's labeling; begin at earliest signs of disease); 400 mg 3 times/day for 5 days has also been reported
Chronic suppression: 400 mg twice daily or 200 mg 3-5 times/day, for up to 12 months followed by re-evaluation (per manufacturer's labeling); 400-1200 mg/day in 2-3 divided doses has also been reported
Topical: Immunocompromised: Ointment: Initial episode: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Herpes labialis (cold sores): Topical: Apply 5 times/day for 4 days
Herpes zoster (shingles):
Oral: Immunocompetent: 800 mg every 4 hours (5 times/day) for 7-10 days
I.V.: Immunocompromised: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 days
HSV encephalitis: I.V.: 10 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); 10-15 mg/kg/dose every 8 hours for 14-21 days also reported
Mucocutaneous HSV:
I.V.: Immunocompromised: 5 mg/kg/dose every 8 hours for 7 days (per manufacturer's labeling); dosing for up to 14 days also reported
Oral: Immunocompromised (unlabeled use): 400 mg 5 times a day for 7-14 days
Topical: Ointment: Nonlife-threatening, immunocompromised: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral: >40 kg (immunocompetent): 800 mg/dose 4 times a day for 5 days
I.V.:
Manufacturer's labeling (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised): 10-15 mg/kg/dose every 8 hours for 7-10 days
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 200 mg 3 times/day or 400 mg 2 times/day
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days)
Oral: 200 mg 3 times/day
I.V.: 250 mg/m2/dose every 12 hours
Prevention of VZV reactivation in allogeneic HSCT (unlabeled use):NCCN guidelines: Oral: 800 mg twice a day
Prevention of CMV reactivation in low-risk allogeneic HSCT (unlabeled use):NCCN guidelines:Note: Requires close monitoring (due to weak activity); not for use in patients at high risk for CMV disease: Oral: 800 mg 4 times/day
Treatment of disseminated HSV or VZV or empiric treatment of suspected encephalitis in immunocompromised patients with cancer: (unlabeled use):NCCN guidelines: I.V.: 10-12 mg/kg/dose every 8 hours
DOSING: PEDIATRIC — Note: Obese patients should be dosed using ideal body weight
(For additional information see "Acyclovir: Pediatric drug information")
Genital HSV:
I.V.: Children ≥ 12 years: Refer to adult dosing.
Oral:
Initial episode (unlabeled use): 40-80 mg/kg/day divided into 3-4 doses for 5-10 days (maximum: 1 g/day)
Chronic suppression (unlabeled use; limited data): 80 mg/kg/day in 3 divided doses (maximum: 1 g/day), re-evaluate after 12 months of treatment
Herpes labialis (cold sores): Topical: Children ≥ 12 years: Refer to adult dosing.
Herpes zoster (shingles): I.V.:
Children <12 years (immunocompromised): 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
HSV encephalitis: I.V.:
Children 3 months to 12 years: 20 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); dosing for 14-21 days also reported
Children ≥ 12 years: Refer to adult dosing.
Mucocutaneous HSV: I.V.:
Children <12 years (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
Neonatal HSV: I.V.: Neonate: Birth to 3 months: 10 mg/kg/dose every 8 hours for 10 days (manufacturer's labeling); 15 mg/kg/dose or 20 mg/kg/dose every 8 hours for 14-21 days has also been reported
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral:Note: The AIDSinfo guidelines recommended duration of therapy is 7-10 days or until no new lesions for 48 hours (for patients with mild varicella and no or moderate immune suppression).
Children ≥ 2 years and ≤ 40 kg (immunocompetent): 20 mg/kg/dose (up to 800 mg/dose) 4 times/day for 5 days
Children >40 kg: Refer to adult dosing.
I.V.:
Manufacturer's labeling (immunocompromised):
Children <12 years: 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised):
Children <1 year: 10 mg/kg/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Children ≥ 1 year: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Adolescents: Refer to adult dosing.
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 80 mg/kg/day in 3-4 divided doses
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days): I.V.: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Oral:
Clcr 10-25 mL/minute/1.73 m2: Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 8 hours
Clcr <10 mL/minute/1.73 m2:
Normal dosing regimen 200 mg every 4 hours or 400 mg every 12 hours: Administer 200 mg every 12 hours
Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 12 hours
I.V.:
Clcr 25-50 mL/minute/1.73 m2: Administer recommended dose every 12 hours
Clcr 10-25 mL/minute/1.73 m2: Administer recommended dose every 24 hours
Clcr <10 mL/minute/1.73 m2: Administer 50% of recommended dose every 24 hours
Hemodialysis: Administer dose after dialysis
Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of normal dose once daily; no supplemental dose needed
Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 L/hour) and should not supersede clinical judgment:
CVVH or CVVHD/CVVHDF: 5-7.5 mg/kg every 24 hours
Note: The higher dose of 7.5 mg/kg is recommended for infections with CNS involvement (Trotman, 2005).
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution, as sodium: 500 mg [base strength], 1000 mg [base strength]
Injection, solution, as sodium [preservative free]: 50 mg/mL (10 mL, 20 mL) [base strength]
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL (480 mL)
Zovirax®: 200 mg/5 mL (480 mL) [banana flavor]
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
DOSAGE FORMS: CONCISE
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution: 500 mg, 1000 mg
Injection, solution [preservative free]: 50 mg/mL (10 mL, 20 mL)
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL
Zovirax®: 200 mg/5 mL
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
GENERIC EQUIVALENT AVAILABLE — Yes: Excludes cream, ointment
ADMINISTRATION
Oral: May be administered with or without food.
I.V.: Avoid rapid infusion; infuse over 1 hour to prevent renal damage; maintain adequate hydration of patient; check for phlebitis and rotate infusion sites. Avoid I.M. or SubQ administration.
Topical: Not for use in the eye. Apply using a finger cot or rubber glove to avoid transmission to other parts of the body or to other persons.
COMPATIBILITY — Stable in D5W, D5NS, D51/4NS, D51/2NS, LR, NS.
Incompatible with blood products and protein-containing solutions.
Y-site administration: Compatible: Allopurinol, amikacin, amphotericin B cholesteryl sulfate complex, ampicillin, anidulafungin, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, clindamycin, co-trimoxazole, dexamethasone sodium phosphate, dimenhydrinate, diphenhydramine, docetaxel, doxorubicin liposome, doxycycline, erythromycin lactobionate, etoposide phosphate, famotidine, filgrastim, fluconazole, gallium nitrate, gentamicin, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, linezolid, lorazepam, magnesium sulfate, melphalan, methylprednisolone sodium succinate, metoclopramide, metronidazole, milrinone, multivitamins, nafcillin, oxacillin, paclitaxel, pemetrexed, penicillin G potassium, pentobarbital, piperacillin, potassium chloride, propofol, ranitidine, remifentanil, sodium bicarbonate, teniposide, theophylline, thiotepa, tobramycin, vancomycin, zidovudine. Incompatible: Amifostine, amsacrine, aztreonam, cefepime, dobutamine, dopamine, fludarabine, foscarnet, gemcitabine, idarubicin, levofloxacin, ondansetron, piperacillin/tazobactam, sargramostim, tacrolimus, vinorelbine. Variable (consult detailed reference): Cisatracurium, diltiazem, meperidine, meropenem, morphine, TPN.
Compatibility in syringe: Incompatible: Caffeine citrate, pantoprazole.
Compatibility when admixed: Compatible: Fluconazole. Incompatible: Dobutamine, dopamine. Variable (consult detailed reference): Meropenem.
USE — Treatment of genital herpes simplex virus (HSV), herpes labialis (cold sores), herpes zoster (shingles), HSV encephalitis, neonatal HSV, mucocutaneous HSV in immunocompromised patients, varicella-zoster (chickenpox)
USE - UNLABELED / INVESTIGATIONAL — Prevention of HSV reactivation in HIV-positive patients; prevention of HSV reactivation in hematopoietic stem cell transplant (HSCT); prevention of HSV reactivation during periods of neutropenia in patients with cancer; prevention of varicella zoster virus (VZV) reactivation in allogenic HSCT; prevention of CMV reactivation in low-risk allogeneic HSCT; treatment of disseminated HSV or VZV in immunocompromised patients with cancer; empiric treatment of suspected encephalitis in immunocompromised patients with cancer
ADVERSE REACTIONS SIGNIFICANT
Systemic: Oral:
>10%: Central nervous system: Malaise (≤ 12%)
1% to 10%:
Central nervous system: Headache (≤ 2%)
Gastrointestinal: Nausea (2% to 5%), vomiting (≤ 3%), diarrhea (2% to 3%)
Systemic: Parenteral:
1% to 10%:
Dermatologic: Hives (2%), itching (2%), rash (2%)
Gastrointestinal: Nausea/vomiting (7%)
Hepatic: Liver function tests increased (1% to 2%)
Local: Inflammation at injection site or phlebitis (9%)
Renal: BUN increased (5% to 10%), creatinine increased (5% to 10%), acute renal failure
Topical:
>10%: Dermatologic: Mild pain, burning, or stinging (ointment 30%)
1% to 10%: Dermatologic: Pruritus (ointment 4%), itching
All forms: <1% (Limited to important or life-threatening): Abdominal pain, aggression, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, confusion, consciousness decreased, delirium, desquamation, disseminated intravascular coagulopathy (DIC), dizziness, dry lips, dysarthria, encephalopathy, erythema multiforme, fatigue, fever, gastrointestinal distress, hallucinations, hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypotension, insomnia, jaundice, leukocytoclastic vasculitis, leukocytosis, leukopenia, local tissue necrosis (following extravasation), lymphadenopathy, mental depression, myalgia, neutrophilia, pain, paresthesia, peripheral edema, photosensitization, pruritus, psychosis, renal failure, renal pain, seizure, somnolence, sore throat, Stevens-Johnson syndrome, thrombocytopenia, thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), thrombocytosis, toxic epidermal necrolysis, tremor, urticaria, visual disturbances
CONTRAINDICATIONS — Hypersensitivity to acyclovir, valacyclovir, or any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Renal effects: Renal failure (sometimes fatal) has been reported. Dehydration, pre-existing renal disease and nephrotoxic drugs increase risk; infuse over at least 1 hour to reduce risk of renal tubular damage. Thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has been reported in immunocompromised patients receiving acyclovir.
Disease-related concerns: Genital herpes: Appropriate use: Physical contact should be avoided when lesions are present; transmission may also occur in the absence of symptoms. Treatment should begin with the first signs or symptoms. Herpes labialis: Appropriate use: For external use only to the lips and face; do not apply to eye or inside the mouth or nose. Treatment should begin with the first signs or symptoms. Herpes zoster: Appropriate use: Therapy should be started within 72 hours of appearance of rash to be effective. Renal impairment: Use with caution in patients with pre-existing renal impairment; dosage adjustments recommended. Varicella-zoster: Appropriate use: Treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella, but may be effective in patients at increased risk of moderate-to-severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).
Concurrent drug therapy issues: Nephrotoxic drugs: Use with caution in patients receiving other nephrotoxic drugs.
Special populations: Elderly: Use with caution in the elderly; higher risk for CNS, renal, and gastrointestinal adverse events. Immunocompromised patients: Use with caution in immunocompromised patients. Pediatrics: Safety and efficacy of oral formulations have not been established in children <2 years of age.
Dosage form specific issues: Injection: Use I.V. preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia.
Other warnings/precautions: Adequate hydration: Maintain adequate hydration during oral or intravenous therapy.
DRUG INTERACTIONS
Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapy
Tenofovir: Acyclovir-Valacyclovir may decrease the excretion of Tenofovir. Risk C: Monitor therapy
Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Risk C: Monitor therapy
Zoster Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine. Management: When possible, discontinue antiviral agents with anti-zoster activity (i.e., acyclovir, valacyclovir, famciclovir) for at least 24 hours prior to and 14 days after receiving a live attenuated zoster vaccine. Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: Does not affect absorption of oral acyclovir.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. Acyclovir has been shown to cross the human placenta. There are no adequate and well-controlled studies in pregnant women. Results from a pregnancy registry, established in 1984 and closed in 1999, did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. However, due to the small size of the registry and lack of long-term data, the manufacturer recommends using during pregnancy with caution and only when clearly needed. Data from the pregnancy registry may be obtained from GlaxoSmithKline.
LACTATION — Enters breast milk/use with caution (AAP rates "compatible")
BREAST-FEEDING CONSIDERATIONS — Nursing mothers with herpetic lesions near or on the breast should avoid breast-feeding. Limited data suggest exposure to the nursing infant of ~0.3 mg/kg/day following oral administration of acyclovir to the mother.
DIETARY CONSIDERATIONS — May be taken with or without food. Acyclovir 500 mg injection contains sodium ~50 mg (~2 mEq).
PRICING — (data from drugstore.com)
Capsules (Acyclovir)
200 mg (30): $12.99
Capsules (Zovirax)
200 mg (30): $92.39
Cream (Zovirax)
5% (2): $66.96
5% (5): $147.47
Ointment (Zovirax)
5% (15): $165.27
Suspension (Acyclovir)
200 mg/5 mL (473): $123.97
Suspension (Zovirax)
200 mg/5 mL (473): $252.77
Tablets (Acyclovir)
400 mg (60): $28.99
800 mg (30): $24.99
Tablets (Zovirax)
400 mg (60): $344.72
800 mg (30): $324.98
MONITORING PARAMETERS — Urinalysis, BUN, serum creatinine, liver enzymes, CBC
CANADIAN BRAND NAMES — Apo-Acyclovir®; Gen-Acyclovir; Novo-Acyclovir; Nu-Acyclovir; ratio-Acyclovir; Zovirax®
INTERNATIONAL BRAND NAMES — Abbovir (PL); ACERPES (DE); Acic Creme (DE); Aciclobeta (AU); Acicloftal (IT); Aciclor (VE); Aciclosina (PE); Aciclovir (PL); aciclovir von ct (LU); Aciclovir-BC IV (AU); Acicvir (NZ); Acifur (MX); Acihexal (AU); Acivir Cream (IL, IN); Acivir Eye (IN); Acix (PL); Aclova (KP); Aclovir (HR, TH, TW); Aclovirax (HK); ACS (KP); Activir (FR); Acyclo-V (AU, BH, NZ); Acyclostad (PL); Acyclovir (PL); Acyclovir Stada (PL); Acyhex (PH); Acyklowir (PL); Acylene (MY); Acyrova (KP); Acyvir (EC, HK, IT); Aias (KP); Antivir (PL); Apo-Acyclovir (PL); Avorax (HK, MY, SG); Avorax Cream (MY); Awirol (PL); Cicloferon (MX); Cicloviral (CO); Ciklovir (HU); Clinovir (ID, TH); Clirbest (MX); Clorixan (MX); Clovir (BR, KP); Cloviran (CN); Clyvorax (MX); Colsor (TH); Cusiviral (HK, MY, PL, SG); Cyclivex (ZA); Cyclomed (IL); Cyclorax (HK); Cyclostad (PH); Cyclovir (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Cyllanvir (PH); Danovir (SG); Declovir (HK); Deherp (TH, TW); Dravyr (SG); Duvimex (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Ecuvir (EC); Entir (SG, TH); Erlvirax (SG); Euroclovir (HK); Eurovir (PY); Exavir (BR); Expit (UY); Geavir (DK, SE); Genovix (MX); Hascovir (PL); Helvevir (CH); Herax (ID); Hercivir (MX); Herpefug (DE); Herpesin (HU, PL); Herpetad (CR, DO, GT, HN, NI, PA, SV); Herpevir (FR); Herpex (BH, IN, PL); Herpizyg (TH); Herpoviric (DE); Herpoviric Rp Creme (DE); Heviran (PL); Ignis (MX); Inmerax (CN); Jersin (MX); Juviral (DE); Laciken (MX); Lermex (TH); Licovir (ID); Lisovyr (AR, CN); Lovir (AU, HK); Lovir Cold Sore Cream (AU); Lovire (ZA); Mapox (LU); Marvir (TH); Maynor (ES); Medovir (AE, BF, BG, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, OM, QA, SA, SC, SD, SG, SL, SN, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Molavir (ID); Norum (TH); Oppvir (TH, TW); Opthavir (MX); Ozvir (AU); Poviral (EC); Proviral (AR); Qualiclovir (HK); Quavir (ID); Ranvir (TH); Ranviran (PL); Reclovax (TH); Remex (FR); Skirax (TW); Sophivir Ungena (MX); Supra-Vir (IL); Supraviran (DE, LU, PL); Supraviran Creme (AE, BH, CY, DE, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Syntovir (HK); Telviran (HU); Vacrax (MY); Vacrovir (KP); Vermis (TH); Vicorax (TH, TW); Victoclir (MX); Viracir (PL); Viralex-DS (PH); Viralis (ID); Virax (KP); Virest (MY, SG); Virestat (MX); Virex (CO); Virherpes (ES); Virless (CL, SG, TW); Viroclear (HK); Virogon (TH); Virokill (HU); Virolan (TW); Virolex (HR, HU, PL); Viromed (TH); Virucid (HK); Virules (HK); Vivir (KP); Warviron (HK); Zeven Cream (MY); Zevin (TH); Zirconia (MX); Ziverone (MX); Zodiac (KP); Zoral (HK, SG); Zoral Cream (MY); Zorax (SG); Zoter (ID); Zoteran (PH); Zovir (DK); Zovirax (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BO, BR, BS, BZ, CH, CI, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, ID, IE, IL, IN, IQ, IR, IT, JM, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PR, PT, PY, QA, RU, SA, SC, SD, SE, SG, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UG, UY, VE, YE, ZA, ZM, ZW); Zovirax [tabs./susp./ungt.] (PL); Zyclorax (ID); Zyvir (KE)
MECHANISM OF ACTION — Acyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.
PHARMACODYNAMICS / KINETICS
Absorption: Oral: 15% to 30%
Distribution: Vd: 0.8 L/kg (63.6 L): Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, CSF)
Protein binding: 9% to 33%
Metabolism: Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes
Bioavailability: Oral: 10% to 20% with normal renal function (bioavailability decreases with increased dose)
Half-life elimination: Terminal: Neonates: 4 hours; Children 1-12 years: 2-3 hours; Adults: 3 hours
Time to peak, serum: Oral: Within 1.5-2 hours
Excretion: Urine (62% to 90% as unchanged drug and metabolite)
PATIENT INFORMATION — This is not a cure for herpes (recurrences tend to continually reappear every 3-6 months after original infection), nor will this medication reduce the risk of transmission to others when lesions are present; avoid sexual intercourse when visible lesions are present. Take as directed for full course of therapy; do not discontinue even if feeling better. Oral doses may be taken with food.
Sound-alike/look-alike issues:
Acyclovir may be confused with ganciclovir, Retrovir®, valACYclovir
Zovirax® may be confused with Valtrex®, Zithromax®, Zostrix®, Zyloprim®, Zyvox®
International issues:
Opthavir® [Mexico] may be confused with Optivar® which is a brand name for azelastine in the U.S.
U.S. BRAND NAMES — Zovirax®
PHARMACOLOGIC CATEGORY
Antiviral Agent
Antiviral Agent, Topical
DOSING: ADULTS — Note: Obese patients should be dosed using ideal body weight
Genital HSV:
I.V.: Immunocompetent: Initial episode, severe: 5 mg/kg/dose every 8 hours for 5-7 days
Oral:
Initial episode: 200 mg every 4 hours while awake (5 times/day) for 10 days (per manufacturer's labeling); 400 mg 3 times/day for 5-10 days has also been reported
Recurrence: 200 mg every 4 hours while awake (5 times/day) for 5 days (per manufacturer's labeling; begin at earliest signs of disease); 400 mg 3 times/day for 5 days has also been reported
Chronic suppression: 400 mg twice daily or 200 mg 3-5 times/day, for up to 12 months followed by re-evaluation (per manufacturer's labeling); 400-1200 mg/day in 2-3 divided doses has also been reported
Topical: Immunocompromised: Ointment: Initial episode: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Herpes labialis (cold sores): Topical: Apply 5 times/day for 4 days
Herpes zoster (shingles):
Oral: Immunocompetent: 800 mg every 4 hours (5 times/day) for 7-10 days
I.V.: Immunocompromised: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 days
HSV encephalitis: I.V.: 10 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); 10-15 mg/kg/dose every 8 hours for 14-21 days also reported
Mucocutaneous HSV:
I.V.: Immunocompromised: 5 mg/kg/dose every 8 hours for 7 days (per manufacturer's labeling); dosing for up to 14 days also reported
Oral: Immunocompromised (unlabeled use): 400 mg 5 times a day for 7-14 days
Topical: Ointment: Nonlife-threatening, immunocompromised: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral: >40 kg (immunocompetent): 800 mg/dose 4 times a day for 5 days
I.V.:
Manufacturer's labeling (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised): 10-15 mg/kg/dose every 8 hours for 7-10 days
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 200 mg 3 times/day or 400 mg 2 times/day
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days)
Oral: 200 mg 3 times/day
I.V.: 250 mg/m2/dose every 12 hours
Prevention of VZV reactivation in allogeneic HSCT (unlabeled use):NCCN guidelines: Oral: 800 mg twice a day
Prevention of CMV reactivation in low-risk allogeneic HSCT (unlabeled use):NCCN guidelines:Note: Requires close monitoring (due to weak activity); not for use in patients at high risk for CMV disease: Oral: 800 mg 4 times/day
Treatment of disseminated HSV or VZV or empiric treatment of suspected encephalitis in immunocompromised patients with cancer: (unlabeled use):NCCN guidelines: I.V.: 10-12 mg/kg/dose every 8 hours
DOSING: PEDIATRIC — Note: Obese patients should be dosed using ideal body weight
(For additional information see "Acyclovir: Pediatric drug information")
Genital HSV:
I.V.: Children ≥ 12 years: Refer to adult dosing.
Oral:
Initial episode (unlabeled use): 40-80 mg/kg/day divided into 3-4 doses for 5-10 days (maximum: 1 g/day)
Chronic suppression (unlabeled use; limited data): 80 mg/kg/day in 3 divided doses (maximum: 1 g/day), re-evaluate after 12 months of treatment
Herpes labialis (cold sores): Topical: Children ≥ 12 years: Refer to adult dosing.
Herpes zoster (shingles): I.V.:
Children <12 years (immunocompromised): 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
HSV encephalitis: I.V.:
Children 3 months to 12 years: 20 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); dosing for 14-21 days also reported
Children ≥ 12 years: Refer to adult dosing.
Mucocutaneous HSV: I.V.:
Children <12 years (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
Neonatal HSV: I.V.: Neonate: Birth to 3 months: 10 mg/kg/dose every 8 hours for 10 days (manufacturer's labeling); 15 mg/kg/dose or 20 mg/kg/dose every 8 hours for 14-21 days has also been reported
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral:Note: The AIDSinfo guidelines recommended duration of therapy is 7-10 days or until no new lesions for 48 hours (for patients with mild varicella and no or moderate immune suppression).
Children ≥ 2 years and ≤ 40 kg (immunocompetent): 20 mg/kg/dose (up to 800 mg/dose) 4 times/day for 5 days
Children >40 kg: Refer to adult dosing.
I.V.:
Manufacturer's labeling (immunocompromised):
Children <12 years: 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised):
Children <1 year: 10 mg/kg/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Children ≥ 1 year: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Adolescents: Refer to adult dosing.
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 80 mg/kg/day in 3-4 divided doses
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days): I.V.: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Oral:
Clcr 10-25 mL/minute/1.73 m2: Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 8 hours
Clcr <10 mL/minute/1.73 m2:
Normal dosing regimen 200 mg every 4 hours or 400 mg every 12 hours: Administer 200 mg every 12 hours
Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 12 hours
I.V.:
Clcr 25-50 mL/minute/1.73 m2: Administer recommended dose every 12 hours
Clcr 10-25 mL/minute/1.73 m2: Administer recommended dose every 24 hours
Clcr <10 mL/minute/1.73 m2: Administer 50% of recommended dose every 24 hours
Hemodialysis: Administer dose after dialysis
Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of normal dose once daily; no supplemental dose needed
Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 L/hour) and should not supersede clinical judgment:
CVVH or CVVHD/CVVHDF: 5-7.5 mg/kg every 24 hours
Note: The higher dose of 7.5 mg/kg is recommended for infections with CNS involvement (Trotman, 2005).
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution, as sodium: 500 mg [base strength], 1000 mg [base strength]
Injection, solution, as sodium [preservative free]: 50 mg/mL (10 mL, 20 mL) [base strength]
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL (480 mL)
Zovirax®: 200 mg/5 mL (480 mL) [banana flavor]
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
DOSAGE FORMS: CONCISE
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution: 500 mg, 1000 mg
Injection, solution [preservative free]: 50 mg/mL (10 mL, 20 mL)
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL
Zovirax®: 200 mg/5 mL
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
GENERIC EQUIVALENT AVAILABLE — Yes: Excludes cream, ointment
ADMINISTRATION
Oral: May be administered with or without food.
I.V.: Avoid rapid infusion; infuse over 1 hour to prevent renal damage; maintain adequate hydration of patient; check for phlebitis and rotate infusion sites. Avoid I.M. or SubQ administration.
Topical: Not for use in the eye. Apply using a finger cot or rubber glove to avoid transmission to other parts of the body or to other persons.
COMPATIBILITY — Stable in D5W, D5NS, D51/4NS, D51/2NS, LR, NS.
Incompatible with blood products and protein-containing solutions.
Y-site administration: Compatible: Allopurinol, amikacin, amphotericin B cholesteryl sulfate complex, ampicillin, anidulafungin, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, clindamycin, co-trimoxazole, dexamethasone sodium phosphate, dimenhydrinate, diphenhydramine, docetaxel, doxorubicin liposome, doxycycline, erythromycin lactobionate, etoposide phosphate, famotidine, filgrastim, fluconazole, gallium nitrate, gentamicin, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, linezolid, lorazepam, magnesium sulfate, melphalan, methylprednisolone sodium succinate, metoclopramide, metronidazole, milrinone, multivitamins, nafcillin, oxacillin, paclitaxel, pemetrexed, penicillin G potassium, pentobarbital, piperacillin, potassium chloride, propofol, ranitidine, remifentanil, sodium bicarbonate, teniposide, theophylline, thiotepa, tobramycin, vancomycin, zidovudine. Incompatible: Amifostine, amsacrine, aztreonam, cefepime, dobutamine, dopamine, fludarabine, foscarnet, gemcitabine, idarubicin, levofloxacin, ondansetron, piperacillin/tazobactam, sargramostim, tacrolimus, vinorelbine. Variable (consult detailed reference): Cisatracurium, diltiazem, meperidine, meropenem, morphine, TPN.
Compatibility in syringe: Incompatible: Caffeine citrate, pantoprazole.
Compatibility when admixed: Compatible: Fluconazole. Incompatible: Dobutamine, dopamine. Variable (consult detailed reference): Meropenem.
USE — Treatment of genital herpes simplex virus (HSV), herpes labialis (cold sores), herpes zoster (shingles), HSV encephalitis, neonatal HSV, mucocutaneous HSV in immunocompromised patients, varicella-zoster (chickenpox)
USE - UNLABELED / INVESTIGATIONAL — Prevention of HSV reactivation in HIV-positive patients; prevention of HSV reactivation in hematopoietic stem cell transplant (HSCT); prevention of HSV reactivation during periods of neutropenia in patients with cancer; prevention of varicella zoster virus (VZV) reactivation in allogenic HSCT; prevention of CMV reactivation in low-risk allogeneic HSCT; treatment of disseminated HSV or VZV in immunocompromised patients with cancer; empiric treatment of suspected encephalitis in immunocompromised patients with cancer
ADVERSE REACTIONS SIGNIFICANT
Systemic: Oral:
>10%: Central nervous system: Malaise (≤ 12%)
1% to 10%:
Central nervous system: Headache (≤ 2%)
Gastrointestinal: Nausea (2% to 5%), vomiting (≤ 3%), diarrhea (2% to 3%)
Systemic: Parenteral:
1% to 10%:
Dermatologic: Hives (2%), itching (2%), rash (2%)
Gastrointestinal: Nausea/vomiting (7%)
Hepatic: Liver function tests increased (1% to 2%)
Local: Inflammation at injection site or phlebitis (9%)
Renal: BUN increased (5% to 10%), creatinine increased (5% to 10%), acute renal failure
Topical:
>10%: Dermatologic: Mild pain, burning, or stinging (ointment 30%)
1% to 10%: Dermatologic: Pruritus (ointment 4%), itching
All forms: <1% (Limited to important or life-threatening): Abdominal pain, aggression, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, confusion, consciousness decreased, delirium, desquamation, disseminated intravascular coagulopathy (DIC), dizziness, dry lips, dysarthria, encephalopathy, erythema multiforme, fatigue, fever, gastrointestinal distress, hallucinations, hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypotension, insomnia, jaundice, leukocytoclastic vasculitis, leukocytosis, leukopenia, local tissue necrosis (following extravasation), lymphadenopathy, mental depression, myalgia, neutrophilia, pain, paresthesia, peripheral edema, photosensitization, pruritus, psychosis, renal failure, renal pain, seizure, somnolence, sore throat, Stevens-Johnson syndrome, thrombocytopenia, thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), thrombocytosis, toxic epidermal necrolysis, tremor, urticaria, visual disturbances
CONTRAINDICATIONS — Hypersensitivity to acyclovir, valacyclovir, or any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Renal effects: Renal failure (sometimes fatal) has been reported. Dehydration, pre-existing renal disease and nephrotoxic drugs increase risk; infuse over at least 1 hour to reduce risk of renal tubular damage. Thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has been reported in immunocompromised patients receiving acyclovir.
Disease-related concerns: Genital herpes: Appropriate use: Physical contact should be avoided when lesions are present; transmission may also occur in the absence of symptoms. Treatment should begin with the first signs or symptoms. Herpes labialis: Appropriate use: For external use only to the lips and face; do not apply to eye or inside the mouth or nose. Treatment should begin with the first signs or symptoms. Herpes zoster: Appropriate use: Therapy should be started within 72 hours of appearance of rash to be effective. Renal impairment: Use with caution in patients with pre-existing renal impairment; dosage adjustments recommended. Varicella-zoster: Appropriate use: Treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella, but may be effective in patients at increased risk of moderate-to-severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).
Concurrent drug therapy issues: Nephrotoxic drugs: Use with caution in patients receiving other nephrotoxic drugs.
Special populations: Elderly: Use with caution in the elderly; higher risk for CNS, renal, and gastrointestinal adverse events. Immunocompromised patients: Use with caution in immunocompromised patients. Pediatrics: Safety and efficacy of oral formulations have not been established in children <2 years of age.
Dosage form specific issues: Injection: Use I.V. preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia.
Other warnings/precautions: Adequate hydration: Maintain adequate hydration during oral or intravenous therapy.
DRUG INTERACTIONS
Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapy
Tenofovir: Acyclovir-Valacyclovir may decrease the excretion of Tenofovir. Risk C: Monitor therapy
Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Risk C: Monitor therapy
Zoster Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine. Management: When possible, discontinue antiviral agents with anti-zoster activity (i.e., acyclovir, valacyclovir, famciclovir) for at least 24 hours prior to and 14 days after receiving a live attenuated zoster vaccine. Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: Does not affect absorption of oral acyclovir.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. Acyclovir has been shown to cross the human placenta. There are no adequate and well-controlled studies in pregnant women. Results from a pregnancy registry, established in 1984 and closed in 1999, did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. However, due to the small size of the registry and lack of long-term data, the manufacturer recommends using during pregnancy with caution and only when clearly needed. Data from the pregnancy registry may be obtained from GlaxoSmithKline.
LACTATION — Enters breast milk/use with caution (AAP rates "compatible")
BREAST-FEEDING CONSIDERATIONS — Nursing mothers with herpetic lesions near or on the breast should avoid breast-feeding. Limited data suggest exposure to the nursing infant of ~0.3 mg/kg/day following oral administration of acyclovir to the mother.
DIETARY CONSIDERATIONS — May be taken with or without food. Acyclovir 500 mg injection contains sodium ~50 mg (~2 mEq).
PRICING — (data from drugstore.com)
Capsules (Acyclovir)
200 mg (30): $12.99
Capsules (Zovirax)
200 mg (30): $92.39
Cream (Zovirax)
5% (2): $66.96
5% (5): $147.47
Ointment (Zovirax)
5% (15): $165.27
Suspension (Acyclovir)
200 mg/5 mL (473): $123.97
Suspension (Zovirax)
200 mg/5 mL (473): $252.77
Tablets (Acyclovir)
400 mg (60): $28.99
800 mg (30): $24.99
Tablets (Zovirax)
400 mg (60): $344.72
800 mg (30): $324.98
MONITORING PARAMETERS — Urinalysis, BUN, serum creatinine, liver enzymes, CBC
CANADIAN BRAND NAMES — Apo-Acyclovir®; Gen-Acyclovir; Novo-Acyclovir; Nu-Acyclovir; ratio-Acyclovir; Zovirax®
INTERNATIONAL BRAND NAMES — Abbovir (PL); ACERPES (DE); Acic Creme (DE); Aciclobeta (AU); Acicloftal (IT); Aciclor (VE); Aciclosina (PE); Aciclovir (PL); aciclovir von ct (LU); Aciclovir-BC IV (AU); Acicvir (NZ); Acifur (MX); Acihexal (AU); Acivir Cream (IL, IN); Acivir Eye (IN); Acix (PL); Aclova (KP); Aclovir (HR, TH, TW); Aclovirax (HK); ACS (KP); Activir (FR); Acyclo-V (AU, BH, NZ); Acyclostad (PL); Acyclovir (PL); Acyclovir Stada (PL); Acyhex (PH); Acyklowir (PL); Acylene (MY); Acyrova (KP); Acyvir (EC, HK, IT); Aias (KP); Antivir (PL); Apo-Acyclovir (PL); Avorax (HK, MY, SG); Avorax Cream (MY); Awirol (PL); Cicloferon (MX); Cicloviral (CO); Ciklovir (HU); Clinovir (ID, TH); Clirbest (MX); Clorixan (MX); Clovir (BR, KP); Cloviran (CN); Clyvorax (MX); Colsor (TH); Cusiviral (HK, MY, PL, SG); Cyclivex (ZA); Cyclomed (IL); Cyclorax (HK); Cyclostad (PH); Cyclovir (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Cyllanvir (PH); Danovir (SG); Declovir (HK); Deherp (TH, TW); Dravyr (SG); Duvimex (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Ecuvir (EC); Entir (SG, TH); Erlvirax (SG); Euroclovir (HK); Eurovir (PY); Exavir (BR); Expit (UY); Geavir (DK, SE); Genovix (MX); Hascovir (PL); Helvevir (CH); Herax (ID); Hercivir (MX); Herpefug (DE); Herpesin (HU, PL); Herpetad (CR, DO, GT, HN, NI, PA, SV); Herpevir (FR); Herpex (BH, IN, PL); Herpizyg (TH); Herpoviric (DE); Herpoviric Rp Creme (DE); Heviran (PL); Ignis (MX); Inmerax (CN); Jersin (MX); Juviral (DE); Laciken (MX); Lermex (TH); Licovir (ID); Lisovyr (AR, CN); Lovir (AU, HK); Lovir Cold Sore Cream (AU); Lovire (ZA); Mapox (LU); Marvir (TH); Maynor (ES); Medovir (AE, BF, BG, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, OM, QA, SA, SC, SD, SG, SL, SN, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Molavir (ID); Norum (TH); Oppvir (TH, TW); Opthavir (MX); Ozvir (AU); Poviral (EC); Proviral (AR); Qualiclovir (HK); Quavir (ID); Ranvir (TH); Ranviran (PL); Reclovax (TH); Remex (FR); Skirax (TW); Sophivir Ungena (MX); Supra-Vir (IL); Supraviran (DE, LU, PL); Supraviran Creme (AE, BH, CY, DE, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Syntovir (HK); Telviran (HU); Vacrax (MY); Vacrovir (KP); Vermis (TH); Vicorax (TH, TW); Victoclir (MX); Viracir (PL); Viralex-DS (PH); Viralis (ID); Virax (KP); Virest (MY, SG); Virestat (MX); Virex (CO); Virherpes (ES); Virless (CL, SG, TW); Viroclear (HK); Virogon (TH); Virokill (HU); Virolan (TW); Virolex (HR, HU, PL); Viromed (TH); Virucid (HK); Virules (HK); Vivir (KP); Warviron (HK); Zeven Cream (MY); Zevin (TH); Zirconia (MX); Ziverone (MX); Zodiac (KP); Zoral (HK, SG); Zoral Cream (MY); Zorax (SG); Zoter (ID); Zoteran (PH); Zovir (DK); Zovirax (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BO, BR, BS, BZ, CH, CI, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, ID, IE, IL, IN, IQ, IR, IT, JM, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PR, PT, PY, QA, RU, SA, SC, SD, SE, SG, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UG, UY, VE, YE, ZA, ZM, ZW); Zovirax [tabs./susp./ungt.] (PL); Zyclorax (ID); Zyvir (KE)
MECHANISM OF ACTION — Acyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.
PHARMACODYNAMICS / KINETICS
Absorption: Oral: 15% to 30%
Distribution: Vd: 0.8 L/kg (63.6 L): Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, CSF)
Protein binding: 9% to 33%
Metabolism: Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes
Bioavailability: Oral: 10% to 20% with normal renal function (bioavailability decreases with increased dose)
Half-life elimination: Terminal: Neonates: 4 hours; Children 1-12 years: 2-3 hours; Adults: 3 hours
Time to peak, serum: Oral: Within 1.5-2 hours
Excretion: Urine (62% to 90% as unchanged drug and metabolite)
PATIENT INFORMATION — This is not a cure for herpes (recurrences tend to continually reappear every 3-6 months after original infection), nor will this medication reduce the risk of transmission to others when lesions are present; avoid sexual intercourse when visible lesions are present. Take as directed for full course of therapy; do not discontinue even if feeling better. Oral doses may be taken with food.
Acyclovir
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Acyclovir may be confused with ganciclovir, Retrovir®, valACYclovir
Zovirax® may be confused with Valtrex®, Zithromax®, Zostrix®, Zyloprim®, Zyvox®
International issues:
Opthavir® [Mexico] may be confused with Optivar® which is a brand name for azelastine in the U.S.
U.S. BRAND NAMES — Zovirax®
PHARMACOLOGIC CATEGORY
Antiviral Agent
Antiviral Agent, Topical
DOSING: ADULTS — Note: Obese patients should be dosed using ideal body weight
Genital HSV:
I.V.: Immunocompetent: Initial episode, severe: 5 mg/kg/dose every 8 hours for 5-7 days
Oral:
Initial episode: 200 mg every 4 hours while awake (5 times/day) for 10 days (per manufacturer's labeling); 400 mg 3 times/day for 5-10 days has also been reported
Recurrence: 200 mg every 4 hours while awake (5 times/day) for 5 days (per manufacturer's labeling; begin at earliest signs of disease); 400 mg 3 times/day for 5 days has also been reported
Chronic suppression: 400 mg twice daily or 200 mg 3-5 times/day, for up to 12 months followed by re-evaluation (per manufacturer's labeling); 400-1200 mg/day in 2-3 divided doses has also been reported
Topical: Immunocompromised: Ointment: Initial episode: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Herpes labialis (cold sores): Topical: Apply 5 times/day for 4 days
Herpes zoster (shingles):
Oral: Immunocompetent: 800 mg every 4 hours (5 times/day) for 7-10 days
I.V.: Immunocompromised: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 days
HSV encephalitis: I.V.: 10 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); 10-15 mg/kg/dose every 8 hours for 14-21 days also reported
Mucocutaneous HSV:
I.V.: Immunocompromised: 5 mg/kg/dose every 8 hours for 7 days (per manufacturer's labeling); dosing for up to 14 days also reported
Oral: Immunocompromised (unlabeled use): 400 mg 5 times a day for 7-14 days
Topical: Ointment: Nonlife-threatening, immunocompromised: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral: >40 kg (immunocompetent): 800 mg/dose 4 times a day for 5 days
I.V.:
Manufacturer's labeling (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised): 10-15 mg/kg/dose every 8 hours for 7-10 days
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 200 mg 3 times/day or 400 mg 2 times/day
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days)
Oral: 200 mg 3 times/day
I.V.: 250 mg/m2/dose every 12 hours
Prevention of VZV reactivation in allogeneic HSCT (unlabeled use):NCCN guidelines: Oral: 800 mg twice a day
Prevention of CMV reactivation in low-risk allogeneic HSCT (unlabeled use):NCCN guidelines:Note: Requires close monitoring (due to weak activity); not for use in patients at high risk for CMV disease: Oral: 800 mg 4 times/day
Treatment of disseminated HSV or VZV or empiric treatment of suspected encephalitis in immunocompromised patients with cancer: (unlabeled use):NCCN guidelines: I.V.: 10-12 mg/kg/dose every 8 hours
DOSING: PEDIATRIC — Note: Obese patients should be dosed using ideal body weight
(For additional information see "Acyclovir: Pediatric drug information")
Genital HSV:
I.V.: Children ≥ 12 years: Refer to adult dosing.
Oral:
Initial episode (unlabeled use): 40-80 mg/kg/day divided into 3-4 doses for 5-10 days (maximum: 1 g/day)
Chronic suppression (unlabeled use; limited data): 80 mg/kg/day in 3 divided doses (maximum: 1 g/day), re-evaluate after 12 months of treatment
Herpes labialis (cold sores): Topical: Children ≥ 12 years: Refer to adult dosing.
Herpes zoster (shingles): I.V.:
Children <12 years (immunocompromised): 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
HSV encephalitis: I.V.:
Children 3 months to 12 years: 20 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); dosing for 14-21 days also reported
Children ≥ 12 years: Refer to adult dosing.
Mucocutaneous HSV: I.V.:
Children <12 years (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
Neonatal HSV: I.V.: Neonate: Birth to 3 months: 10 mg/kg/dose every 8 hours for 10 days (manufacturer's labeling); 15 mg/kg/dose or 20 mg/kg/dose every 8 hours for 14-21 days has also been reported
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral:Note: The AIDSinfo guidelines recommended duration of therapy is 7-10 days or until no new lesions for 48 hours (for patients with mild varicella and no or moderate immune suppression).
Children ≥ 2 years and ≤ 40 kg (immunocompetent): 20 mg/kg/dose (up to 800 mg/dose) 4 times/day for 5 days
Children >40 kg: Refer to adult dosing.
I.V.:
Manufacturer's labeling (immunocompromised):
Children <12 years: 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised):
Children <1 year: 10 mg/kg/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Children ≥ 1 year: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Adolescents: Refer to adult dosing.
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 80 mg/kg/day in 3-4 divided doses
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days): I.V.: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Oral:
Clcr 10-25 mL/minute/1.73 m2: Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 8 hours
Clcr <10 mL/minute/1.73 m2:
Normal dosing regimen 200 mg every 4 hours or 400 mg every 12 hours: Administer 200 mg every 12 hours
Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 12 hours
I.V.:
Clcr 25-50 mL/minute/1.73 m2: Administer recommended dose every 12 hours
Clcr 10-25 mL/minute/1.73 m2: Administer recommended dose every 24 hours
Clcr <10 mL/minute/1.73 m2: Administer 50% of recommended dose every 24 hours
Hemodialysis: Administer dose after dialysis
Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of normal dose once daily; no supplemental dose needed
Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 L/hour) and should not supersede clinical judgment:
CVVH or CVVHD/CVVHDF: 5-7.5 mg/kg every 24 hours
Note: The higher dose of 7.5 mg/kg is recommended for infections with CNS involvement (Trotman, 2005).
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution, as sodium: 500 mg [base strength], 1000 mg [base strength]
Injection, solution, as sodium [preservative free]: 50 mg/mL (10 mL, 20 mL) [base strength]
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL (480 mL)
Zovirax®: 200 mg/5 mL (480 mL) [banana flavor]
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
DOSAGE FORMS: CONCISE
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution: 500 mg, 1000 mg
Injection, solution [preservative free]: 50 mg/mL (10 mL, 20 mL)
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL
Zovirax®: 200 mg/5 mL
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
GENERIC EQUIVALENT AVAILABLE — Yes: Excludes cream, ointment
ADMINISTRATION
Oral: May be administered with or without food.
I.V.: Avoid rapid infusion; infuse over 1 hour to prevent renal damage; maintain adequate hydration of patient; check for phlebitis and rotate infusion sites. Avoid I.M. or SubQ administration.
Topical: Not for use in the eye. Apply using a finger cot or rubber glove to avoid transmission to other parts of the body or to other persons.
COMPATIBILITY — Stable in D5W, D5NS, D51/4NS, D51/2NS, LR, NS.
Incompatible with blood products and protein-containing solutions.
Y-site administration: Compatible: Allopurinol, amikacin, amphotericin B cholesteryl sulfate complex, ampicillin, anidulafungin, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, clindamycin, co-trimoxazole, dexamethasone sodium phosphate, dimenhydrinate, diphenhydramine, docetaxel, doxorubicin liposome, doxycycline, erythromycin lactobionate, etoposide phosphate, famotidine, filgrastim, fluconazole, gallium nitrate, gentamicin, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, linezolid, lorazepam, magnesium sulfate, melphalan, methylprednisolone sodium succinate, metoclopramide, metronidazole, milrinone, multivitamins, nafcillin, oxacillin, paclitaxel, pemetrexed, penicillin G potassium, pentobarbital, piperacillin, potassium chloride, propofol, ranitidine, remifentanil, sodium bicarbonate, teniposide, theophylline, thiotepa, tobramycin, vancomycin, zidovudine. Incompatible: Amifostine, amsacrine, aztreonam, cefepime, dobutamine, dopamine, fludarabine, foscarnet, gemcitabine, idarubicin, levofloxacin, ondansetron, piperacillin/tazobactam, sargramostim, tacrolimus, vinorelbine. Variable (consult detailed reference): Cisatracurium, diltiazem, meperidine, meropenem, morphine, TPN.
Compatibility in syringe: Incompatible: Caffeine citrate, pantoprazole.
Compatibility when admixed: Compatible: Fluconazole. Incompatible: Dobutamine, dopamine. Variable (consult detailed reference): Meropenem.
USE — Treatment of genital herpes simplex virus (HSV), herpes labialis (cold sores), herpes zoster (shingles), HSV encephalitis, neonatal HSV, mucocutaneous HSV in immunocompromised patients, varicella-zoster (chickenpox)
USE - UNLABELED / INVESTIGATIONAL — Prevention of HSV reactivation in HIV-positive patients; prevention of HSV reactivation in hematopoietic stem cell transplant (HSCT); prevention of HSV reactivation during periods of neutropenia in patients with cancer; prevention of varicella zoster virus (VZV) reactivation in allogenic HSCT; prevention of CMV reactivation in low-risk allogeneic HSCT; treatment of disseminated HSV or VZV in immunocompromised patients with cancer; empiric treatment of suspected encephalitis in immunocompromised patients with cancer
ADVERSE REACTIONS SIGNIFICANT
Systemic: Oral:
>10%: Central nervous system: Malaise (≤ 12%)
1% to 10%:
Central nervous system: Headache (≤ 2%)
Gastrointestinal: Nausea (2% to 5%), vomiting (≤ 3%), diarrhea (2% to 3%)
Systemic: Parenteral:
1% to 10%:
Dermatologic: Hives (2%), itching (2%), rash (2%)
Gastrointestinal: Nausea/vomiting (7%)
Hepatic: Liver function tests increased (1% to 2%)
Local: Inflammation at injection site or phlebitis (9%)
Renal: BUN increased (5% to 10%), creatinine increased (5% to 10%), acute renal failure
Topical:
>10%: Dermatologic: Mild pain, burning, or stinging (ointment 30%)
1% to 10%: Dermatologic: Pruritus (ointment 4%), itching
All forms: <1% (Limited to important or life-threatening): Abdominal pain, aggression, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, confusion, consciousness decreased, delirium, desquamation, disseminated intravascular coagulopathy (DIC), dizziness, dry lips, dysarthria, encephalopathy, erythema multiforme, fatigue, fever, gastrointestinal distress, hallucinations, hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypotension, insomnia, jaundice, leukocytoclastic vasculitis, leukocytosis, leukopenia, local tissue necrosis (following extravasation), lymphadenopathy, mental depression, myalgia, neutrophilia, pain, paresthesia, peripheral edema, photosensitization, pruritus, psychosis, renal failure, renal pain, seizure, somnolence, sore throat, Stevens-Johnson syndrome, thrombocytopenia, thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), thrombocytosis, toxic epidermal necrolysis, tremor, urticaria, visual disturbances
CONTRAINDICATIONS — Hypersensitivity to acyclovir, valacyclovir, or any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Renal effects: Renal failure (sometimes fatal) has been reported. Dehydration, pre-existing renal disease and nephrotoxic drugs increase risk; infuse over at least 1 hour to reduce risk of renal tubular damage. Thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has been reported in immunocompromised patients receiving acyclovir.
Disease-related concerns: Genital herpes: Appropriate use: Physical contact should be avoided when lesions are present; transmission may also occur in the absence of symptoms. Treatment should begin with the first signs or symptoms. Herpes labialis: Appropriate use: For external use only to the lips and face; do not apply to eye or inside the mouth or nose. Treatment should begin with the first signs or symptoms. Herpes zoster: Appropriate use: Therapy should be started within 72 hours of appearance of rash to be effective. Renal impairment: Use with caution in patients with pre-existing renal impairment; dosage adjustments recommended. Varicella-zoster: Appropriate use: Treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella, but may be effective in patients at increased risk of moderate-to-severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).
Concurrent drug therapy issues: Nephrotoxic drugs: Use with caution in patients receiving other nephrotoxic drugs.
Special populations: Elderly: Use with caution in the elderly; higher risk for CNS, renal, and gastrointestinal adverse events. Immunocompromised patients: Use with caution in immunocompromised patients. Pediatrics: Safety and efficacy of oral formulations have not been established in children <2 years of age.
Dosage form specific issues: Injection: Use I.V. preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia.
Other warnings/precautions: Adequate hydration: Maintain adequate hydration during oral or intravenous therapy.
DRUG INTERACTIONS
Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapy
Tenofovir: Acyclovir-Valacyclovir may decrease the excretion of Tenofovir. Risk C: Monitor therapy
Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Risk C: Monitor therapy
Zoster Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine. Management: When possible, discontinue antiviral agents with anti-zoster activity (i.e., acyclovir, valacyclovir, famciclovir) for at least 24 hours prior to and 14 days after receiving a live attenuated zoster vaccine. Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: Does not affect absorption of oral acyclovir.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. Acyclovir has been shown to cross the human placenta. There are no adequate and well-controlled studies in pregnant women. Results from a pregnancy registry, established in 1984 and closed in 1999, did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. However, due to the small size of the registry and lack of long-term data, the manufacturer recommends using during pregnancy with caution and only when clearly needed. Data from the pregnancy registry may be obtained from GlaxoSmithKline.
LACTATION — Enters breast milk/use with caution (AAP rates "compatible")
BREAST-FEEDING CONSIDERATIONS — Nursing mothers with herpetic lesions near or on the breast should avoid breast-feeding. Limited data suggest exposure to the nursing infant of ~0.3 mg/kg/day following oral administration of acyclovir to the mother.
DIETARY CONSIDERATIONS — May be taken with or without food. Acyclovir 500 mg injection contains sodium ~50 mg (~2 mEq).
PRICING — (data from drugstore.com)
Capsules (Acyclovir)
200 mg (30): $12.99
Capsules (Zovirax)
200 mg (30): $92.39
Cream (Zovirax)
5% (2): $66.96
5% (5): $147.47
Ointment (Zovirax)
5% (15): $165.27
Suspension (Acyclovir)
200 mg/5 mL (473): $123.97
Suspension (Zovirax)
200 mg/5 mL (473): $252.77
Tablets (Acyclovir)
400 mg (60): $28.99
800 mg (30): $24.99
Tablets (Zovirax)
400 mg (60): $344.72
800 mg (30): $324.98
MONITORING PARAMETERS — Urinalysis, BUN, serum creatinine, liver enzymes, CBC
CANADIAN BRAND NAMES — Apo-Acyclovir®; Gen-Acyclovir; Novo-Acyclovir; Nu-Acyclovir; ratio-Acyclovir; Zovirax®
INTERNATIONAL BRAND NAMES — Abbovir (PL); ACERPES (DE); Acic Creme (DE); Aciclobeta (AU); Acicloftal (IT); Aciclor (VE); Aciclosina (PE); Aciclovir (PL); aciclovir von ct (LU); Aciclovir-BC IV (AU); Acicvir (NZ); Acifur (MX); Acihexal (AU); Acivir Cream (IL, IN); Acivir Eye (IN); Acix (PL); Aclova (KP); Aclovir (HR, TH, TW); Aclovirax (HK); ACS (KP); Activir (FR); Acyclo-V (AU, BH, NZ); Acyclostad (PL); Acyclovir (PL); Acyclovir Stada (PL); Acyhex (PH); Acyklowir (PL); Acylene (MY); Acyrova (KP); Acyvir (EC, HK, IT); Aias (KP); Antivir (PL); Apo-Acyclovir (PL); Avorax (HK, MY, SG); Avorax Cream (MY); Awirol (PL); Cicloferon (MX); Cicloviral (CO); Ciklovir (HU); Clinovir (ID, TH); Clirbest (MX); Clorixan (MX); Clovir (BR, KP); Cloviran (CN); Clyvorax (MX); Colsor (TH); Cusiviral (HK, MY, PL, SG); Cyclivex (ZA); Cyclomed (IL); Cyclorax (HK); Cyclostad (PH); Cyclovir (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Cyllanvir (PH); Danovir (SG); Declovir (HK); Deherp (TH, TW); Dravyr (SG); Duvimex (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Ecuvir (EC); Entir (SG, TH); Erlvirax (SG); Euroclovir (HK); Eurovir (PY); Exavir (BR); Expit (UY); Geavir (DK, SE); Genovix (MX); Hascovir (PL); Helvevir (CH); Herax (ID); Hercivir (MX); Herpefug (DE); Herpesin (HU, PL); Herpetad (CR, DO, GT, HN, NI, PA, SV); Herpevir (FR); Herpex (BH, IN, PL); Herpizyg (TH); Herpoviric (DE); Herpoviric Rp Creme (DE); Heviran (PL); Ignis (MX); Inmerax (CN); Jersin (MX); Juviral (DE); Laciken (MX); Lermex (TH); Licovir (ID); Lisovyr (AR, CN); Lovir (AU, HK); Lovir Cold Sore Cream (AU); Lovire (ZA); Mapox (LU); Marvir (TH); Maynor (ES); Medovir (AE, BF, BG, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, OM, QA, SA, SC, SD, SG, SL, SN, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Molavir (ID); Norum (TH); Oppvir (TH, TW); Opthavir (MX); Ozvir (AU); Poviral (EC); Proviral (AR); Qualiclovir (HK); Quavir (ID); Ranvir (TH); Ranviran (PL); Reclovax (TH); Remex (FR); Skirax (TW); Sophivir Ungena (MX); Supra-Vir (IL); Supraviran (DE, LU, PL); Supraviran Creme (AE, BH, CY, DE, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Syntovir (HK); Telviran (HU); Vacrax (MY); Vacrovir (KP); Vermis (TH); Vicorax (TH, TW); Victoclir (MX); Viracir (PL); Viralex-DS (PH); Viralis (ID); Virax (KP); Virest (MY, SG); Virestat (MX); Virex (CO); Virherpes (ES); Virless (CL, SG, TW); Viroclear (HK); Virogon (TH); Virokill (HU); Virolan (TW); Virolex (HR, HU, PL); Viromed (TH); Virucid (HK); Virules (HK); Vivir (KP); Warviron (HK); Zeven Cream (MY); Zevin (TH); Zirconia (MX); Ziverone (MX); Zodiac (KP); Zoral (HK, SG); Zoral Cream (MY); Zorax (SG); Zoter (ID); Zoteran (PH); Zovir (DK); Zovirax (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BO, BR, BS, BZ, CH, CI, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, ID, IE, IL, IN, IQ, IR, IT, JM, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PR, PT, PY, QA, RU, SA, SC, SD, SE, SG, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UG, UY, VE, YE, ZA, ZM, ZW); Zovirax [tabs./susp./ungt.] (PL); Zyclorax (ID); Zyvir (KE)
MECHANISM OF ACTION — Acyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.
PHARMACODYNAMICS / KINETICS
Absorption: Oral: 15% to 30%
Distribution: Vd: 0.8 L/kg (63.6 L): Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, CSF)
Protein binding: 9% to 33%
Metabolism: Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes
Bioavailability: Oral: 10% to 20% with normal renal function (bioavailability decreases with increased dose)
Half-life elimination: Terminal: Neonates: 4 hours; Children 1-12 years: 2-3 hours; Adults: 3 hours
Time to peak, serum: Oral: Within 1.5-2 hours
Excretion: Urine (62% to 90% as unchanged drug and metabolite)
PATIENT INFORMATION — This is not a cure for herpes (recurrences tend to continually reappear every 3-6 months after original infection), nor will this medication reduce the risk of transmission to others when lesions are present; avoid sexual intercourse when visible lesions are present. Take as directed for full course of therapy; do not discontinue even if feeling better. Oral doses may be taken with food.
Sound-alike/look-alike issues:
Acyclovir may be confused with ganciclovir, Retrovir®, valACYclovir
Zovirax® may be confused with Valtrex®, Zithromax®, Zostrix®, Zyloprim®, Zyvox®
International issues:
Opthavir® [Mexico] may be confused with Optivar® which is a brand name for azelastine in the U.S.
U.S. BRAND NAMES — Zovirax®
PHARMACOLOGIC CATEGORY
Antiviral Agent
Antiviral Agent, Topical
DOSING: ADULTS — Note: Obese patients should be dosed using ideal body weight
Genital HSV:
I.V.: Immunocompetent: Initial episode, severe: 5 mg/kg/dose every 8 hours for 5-7 days
Oral:
Initial episode: 200 mg every 4 hours while awake (5 times/day) for 10 days (per manufacturer's labeling); 400 mg 3 times/day for 5-10 days has also been reported
Recurrence: 200 mg every 4 hours while awake (5 times/day) for 5 days (per manufacturer's labeling; begin at earliest signs of disease); 400 mg 3 times/day for 5 days has also been reported
Chronic suppression: 400 mg twice daily or 200 mg 3-5 times/day, for up to 12 months followed by re-evaluation (per manufacturer's labeling); 400-1200 mg/day in 2-3 divided doses has also been reported
Topical: Immunocompromised: Ointment: Initial episode: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Herpes labialis (cold sores): Topical: Apply 5 times/day for 4 days
Herpes zoster (shingles):
Oral: Immunocompetent: 800 mg every 4 hours (5 times/day) for 7-10 days
I.V.: Immunocompromised: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 days
HSV encephalitis: I.V.: 10 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); 10-15 mg/kg/dose every 8 hours for 14-21 days also reported
Mucocutaneous HSV:
I.V.: Immunocompromised: 5 mg/kg/dose every 8 hours for 7 days (per manufacturer's labeling); dosing for up to 14 days also reported
Oral: Immunocompromised (unlabeled use): 400 mg 5 times a day for 7-14 days
Topical: Ointment: Nonlife-threatening, immunocompromised: 1/2" ribbon of ointment for a 4" square surface area every 3 hours (6 times/day) for 7 days
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral: >40 kg (immunocompetent): 800 mg/dose 4 times a day for 5 days
I.V.:
Manufacturer's labeling (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised): 10-15 mg/kg/dose every 8 hours for 7-10 days
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 200 mg 3 times/day or 400 mg 2 times/day
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days)
Oral: 200 mg 3 times/day
I.V.: 250 mg/m2/dose every 12 hours
Prevention of VZV reactivation in allogeneic HSCT (unlabeled use):NCCN guidelines: Oral: 800 mg twice a day
Prevention of CMV reactivation in low-risk allogeneic HSCT (unlabeled use):NCCN guidelines:Note: Requires close monitoring (due to weak activity); not for use in patients at high risk for CMV disease: Oral: 800 mg 4 times/day
Treatment of disseminated HSV or VZV or empiric treatment of suspected encephalitis in immunocompromised patients with cancer: (unlabeled use):NCCN guidelines: I.V.: 10-12 mg/kg/dose every 8 hours
DOSING: PEDIATRIC — Note: Obese patients should be dosed using ideal body weight
(For additional information see "Acyclovir: Pediatric drug information")
Genital HSV:
I.V.: Children ≥ 12 years: Refer to adult dosing.
Oral:
Initial episode (unlabeled use): 40-80 mg/kg/day divided into 3-4 doses for 5-10 days (maximum: 1 g/day)
Chronic suppression (unlabeled use; limited data): 80 mg/kg/day in 3 divided doses (maximum: 1 g/day), re-evaluate after 12 months of treatment
Herpes labialis (cold sores): Topical: Children ≥ 12 years: Refer to adult dosing.
Herpes zoster (shingles): I.V.:
Children <12 years (immunocompromised): 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
HSV encephalitis: I.V.:
Children 3 months to 12 years: 20 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); dosing for 14-21 days also reported
Children ≥ 12 years: Refer to adult dosing.
Mucocutaneous HSV: I.V.:
Children <12 years (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: Refer to adult dosing.
Neonatal HSV: I.V.: Neonate: Birth to 3 months: 10 mg/kg/dose every 8 hours for 10 days (manufacturer's labeling); 15 mg/kg/dose or 20 mg/kg/dose every 8 hours for 14-21 days has also been reported
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral:Note: The AIDSinfo guidelines recommended duration of therapy is 7-10 days or until no new lesions for 48 hours (for patients with mild varicella and no or moderate immune suppression).
Children ≥ 2 years and ≤ 40 kg (immunocompetent): 20 mg/kg/dose (up to 800 mg/dose) 4 times/day for 5 days
Children >40 kg: Refer to adult dosing.
I.V.:
Manufacturer's labeling (immunocompromised):
Children <12 years: 20 mg/kg/dose every 8 hours for 7 days
Children ≥ 12 years: 10 mg/kg/dose every 8 hours for 7 days
AIDSinfo guidelines (immunocompromised):
Children <1 year: 10 mg/kg/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Children ≥ 1 year: 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7-10 days or until no new lesions for 48 hours
Adolescents: Refer to adult dosing.
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral: 80 mg/kg/day in 3-4 divided doses
Prevention of HSV reactivation in HSCT (unlabeled use):CDC recommendation:Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (~30 days): I.V.: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT
Oral:
Clcr 10-25 mL/minute/1.73 m2: Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 8 hours
Clcr <10 mL/minute/1.73 m2:
Normal dosing regimen 200 mg every 4 hours or 400 mg every 12 hours: Administer 200 mg every 12 hours
Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 12 hours
I.V.:
Clcr 25-50 mL/minute/1.73 m2: Administer recommended dose every 12 hours
Clcr 10-25 mL/minute/1.73 m2: Administer recommended dose every 24 hours
Clcr <10 mL/minute/1.73 m2: Administer 50% of recommended dose every 24 hours
Hemodialysis: Administer dose after dialysis
Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of normal dose once daily; no supplemental dose needed
Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 L/hour) and should not supersede clinical judgment:
CVVH or CVVHD/CVVHDF: 5-7.5 mg/kg every 24 hours
Note: The higher dose of 7.5 mg/kg is recommended for infections with CNS involvement (Trotman, 2005).
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution, as sodium: 500 mg [base strength], 1000 mg [base strength]
Injection, solution, as sodium [preservative free]: 50 mg/mL (10 mL, 20 mL) [base strength]
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL (480 mL)
Zovirax®: 200 mg/5 mL (480 mL) [banana flavor]
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
DOSAGE FORMS: CONCISE
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution: 500 mg, 1000 mg
Injection, solution [preservative free]: 50 mg/mL (10 mL, 20 mL)
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL
Zovirax®: 200 mg/5 mL
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
GENERIC EQUIVALENT AVAILABLE — Yes: Excludes cream, ointment
ADMINISTRATION
Oral: May be administered with or without food.
I.V.: Avoid rapid infusion; infuse over 1 hour to prevent renal damage; maintain adequate hydration of patient; check for phlebitis and rotate infusion sites. Avoid I.M. or SubQ administration.
Topical: Not for use in the eye. Apply using a finger cot or rubber glove to avoid transmission to other parts of the body or to other persons.
COMPATIBILITY — Stable in D5W, D5NS, D51/4NS, D51/2NS, LR, NS.
Incompatible with blood products and protein-containing solutions.
Y-site administration: Compatible: Allopurinol, amikacin, amphotericin B cholesteryl sulfate complex, ampicillin, anidulafungin, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, clindamycin, co-trimoxazole, dexamethasone sodium phosphate, dimenhydrinate, diphenhydramine, docetaxel, doxorubicin liposome, doxycycline, erythromycin lactobionate, etoposide phosphate, famotidine, filgrastim, fluconazole, gallium nitrate, gentamicin, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, linezolid, lorazepam, magnesium sulfate, melphalan, methylprednisolone sodium succinate, metoclopramide, metronidazole, milrinone, multivitamins, nafcillin, oxacillin, paclitaxel, pemetrexed, penicillin G potassium, pentobarbital, piperacillin, potassium chloride, propofol, ranitidine, remifentanil, sodium bicarbonate, teniposide, theophylline, thiotepa, tobramycin, vancomycin, zidovudine. Incompatible: Amifostine, amsacrine, aztreonam, cefepime, dobutamine, dopamine, fludarabine, foscarnet, gemcitabine, idarubicin, levofloxacin, ondansetron, piperacillin/tazobactam, sargramostim, tacrolimus, vinorelbine. Variable (consult detailed reference): Cisatracurium, diltiazem, meperidine, meropenem, morphine, TPN.
Compatibility in syringe: Incompatible: Caffeine citrate, pantoprazole.
Compatibility when admixed: Compatible: Fluconazole. Incompatible: Dobutamine, dopamine. Variable (consult detailed reference): Meropenem.
USE — Treatment of genital herpes simplex virus (HSV), herpes labialis (cold sores), herpes zoster (shingles), HSV encephalitis, neonatal HSV, mucocutaneous HSV in immunocompromised patients, varicella-zoster (chickenpox)
USE - UNLABELED / INVESTIGATIONAL — Prevention of HSV reactivation in HIV-positive patients; prevention of HSV reactivation in hematopoietic stem cell transplant (HSCT); prevention of HSV reactivation during periods of neutropenia in patients with cancer; prevention of varicella zoster virus (VZV) reactivation in allogenic HSCT; prevention of CMV reactivation in low-risk allogeneic HSCT; treatment of disseminated HSV or VZV in immunocompromised patients with cancer; empiric treatment of suspected encephalitis in immunocompromised patients with cancer
ADVERSE REACTIONS SIGNIFICANT
Systemic: Oral:
>10%: Central nervous system: Malaise (≤ 12%)
1% to 10%:
Central nervous system: Headache (≤ 2%)
Gastrointestinal: Nausea (2% to 5%), vomiting (≤ 3%), diarrhea (2% to 3%)
Systemic: Parenteral:
1% to 10%:
Dermatologic: Hives (2%), itching (2%), rash (2%)
Gastrointestinal: Nausea/vomiting (7%)
Hepatic: Liver function tests increased (1% to 2%)
Local: Inflammation at injection site or phlebitis (9%)
Renal: BUN increased (5% to 10%), creatinine increased (5% to 10%), acute renal failure
Topical:
>10%: Dermatologic: Mild pain, burning, or stinging (ointment 30%)
1% to 10%: Dermatologic: Pruritus (ointment 4%), itching
All forms: <1% (Limited to important or life-threatening): Abdominal pain, aggression, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, confusion, consciousness decreased, delirium, desquamation, disseminated intravascular coagulopathy (DIC), dizziness, dry lips, dysarthria, encephalopathy, erythema multiforme, fatigue, fever, gastrointestinal distress, hallucinations, hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypotension, insomnia, jaundice, leukocytoclastic vasculitis, leukocytosis, leukopenia, local tissue necrosis (following extravasation), lymphadenopathy, mental depression, myalgia, neutrophilia, pain, paresthesia, peripheral edema, photosensitization, pruritus, psychosis, renal failure, renal pain, seizure, somnolence, sore throat, Stevens-Johnson syndrome, thrombocytopenia, thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), thrombocytosis, toxic epidermal necrolysis, tremor, urticaria, visual disturbances
CONTRAINDICATIONS — Hypersensitivity to acyclovir, valacyclovir, or any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Renal effects: Renal failure (sometimes fatal) has been reported. Dehydration, pre-existing renal disease and nephrotoxic drugs increase risk; infuse over at least 1 hour to reduce risk of renal tubular damage. Thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has been reported in immunocompromised patients receiving acyclovir.
Disease-related concerns: Genital herpes: Appropriate use: Physical contact should be avoided when lesions are present; transmission may also occur in the absence of symptoms. Treatment should begin with the first signs or symptoms. Herpes labialis: Appropriate use: For external use only to the lips and face; do not apply to eye or inside the mouth or nose. Treatment should begin with the first signs or symptoms. Herpes zoster: Appropriate use: Therapy should be started within 72 hours of appearance of rash to be effective. Renal impairment: Use with caution in patients with pre-existing renal impairment; dosage adjustments recommended. Varicella-zoster: Appropriate use: Treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella, but may be effective in patients at increased risk of moderate-to-severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).
Concurrent drug therapy issues: Nephrotoxic drugs: Use with caution in patients receiving other nephrotoxic drugs.
Special populations: Elderly: Use with caution in the elderly; higher risk for CNS, renal, and gastrointestinal adverse events. Immunocompromised patients: Use with caution in immunocompromised patients. Pediatrics: Safety and efficacy of oral formulations have not been established in children <2 years of age.
Dosage form specific issues: Injection: Use I.V. preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia.
Other warnings/precautions: Adequate hydration: Maintain adequate hydration during oral or intravenous therapy.
DRUG INTERACTIONS
Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapy
Tenofovir: Acyclovir-Valacyclovir may decrease the excretion of Tenofovir. Risk C: Monitor therapy
Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Risk C: Monitor therapy
Zoster Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine. Management: When possible, discontinue antiviral agents with anti-zoster activity (i.e., acyclovir, valacyclovir, famciclovir) for at least 24 hours prior to and 14 days after receiving a live attenuated zoster vaccine. Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: Does not affect absorption of oral acyclovir.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. Acyclovir has been shown to cross the human placenta. There are no adequate and well-controlled studies in pregnant women. Results from a pregnancy registry, established in 1984 and closed in 1999, did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. However, due to the small size of the registry and lack of long-term data, the manufacturer recommends using during pregnancy with caution and only when clearly needed. Data from the pregnancy registry may be obtained from GlaxoSmithKline.
LACTATION — Enters breast milk/use with caution (AAP rates "compatible")
BREAST-FEEDING CONSIDERATIONS — Nursing mothers with herpetic lesions near or on the breast should avoid breast-feeding. Limited data suggest exposure to the nursing infant of ~0.3 mg/kg/day following oral administration of acyclovir to the mother.
DIETARY CONSIDERATIONS — May be taken with or without food. Acyclovir 500 mg injection contains sodium ~50 mg (~2 mEq).
PRICING — (data from drugstore.com)
Capsules (Acyclovir)
200 mg (30): $12.99
Capsules (Zovirax)
200 mg (30): $92.39
Cream (Zovirax)
5% (2): $66.96
5% (5): $147.47
Ointment (Zovirax)
5% (15): $165.27
Suspension (Acyclovir)
200 mg/5 mL (473): $123.97
Suspension (Zovirax)
200 mg/5 mL (473): $252.77
Tablets (Acyclovir)
400 mg (60): $28.99
800 mg (30): $24.99
Tablets (Zovirax)
400 mg (60): $344.72
800 mg (30): $324.98
MONITORING PARAMETERS — Urinalysis, BUN, serum creatinine, liver enzymes, CBC
CANADIAN BRAND NAMES — Apo-Acyclovir®; Gen-Acyclovir; Novo-Acyclovir; Nu-Acyclovir; ratio-Acyclovir; Zovirax®
INTERNATIONAL BRAND NAMES — Abbovir (PL); ACERPES (DE); Acic Creme (DE); Aciclobeta (AU); Acicloftal (IT); Aciclor (VE); Aciclosina (PE); Aciclovir (PL); aciclovir von ct (LU); Aciclovir-BC IV (AU); Acicvir (NZ); Acifur (MX); Acihexal (AU); Acivir Cream (IL, IN); Acivir Eye (IN); Acix (PL); Aclova (KP); Aclovir (HR, TH, TW); Aclovirax (HK); ACS (KP); Activir (FR); Acyclo-V (AU, BH, NZ); Acyclostad (PL); Acyclovir (PL); Acyclovir Stada (PL); Acyhex (PH); Acyklowir (PL); Acylene (MY); Acyrova (KP); Acyvir (EC, HK, IT); Aias (KP); Antivir (PL); Apo-Acyclovir (PL); Avorax (HK, MY, SG); Avorax Cream (MY); Awirol (PL); Cicloferon (MX); Cicloviral (CO); Ciklovir (HU); Clinovir (ID, TH); Clirbest (MX); Clorixan (MX); Clovir (BR, KP); Cloviran (CN); Clyvorax (MX); Colsor (TH); Cusiviral (HK, MY, PL, SG); Cyclivex (ZA); Cyclomed (IL); Cyclorax (HK); Cyclostad (PH); Cyclovir (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Cyllanvir (PH); Danovir (SG); Declovir (HK); Deherp (TH, TW); Dravyr (SG); Duvimex (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Ecuvir (EC); Entir (SG, TH); Erlvirax (SG); Euroclovir (HK); Eurovir (PY); Exavir (BR); Expit (UY); Geavir (DK, SE); Genovix (MX); Hascovir (PL); Helvevir (CH); Herax (ID); Hercivir (MX); Herpefug (DE); Herpesin (HU, PL); Herpetad (CR, DO, GT, HN, NI, PA, SV); Herpevir (FR); Herpex (BH, IN, PL); Herpizyg (TH); Herpoviric (DE); Herpoviric Rp Creme (DE); Heviran (PL); Ignis (MX); Inmerax (CN); Jersin (MX); Juviral (DE); Laciken (MX); Lermex (TH); Licovir (ID); Lisovyr (AR, CN); Lovir (AU, HK); Lovir Cold Sore Cream (AU); Lovire (ZA); Mapox (LU); Marvir (TH); Maynor (ES); Medovir (AE, BF, BG, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, OM, QA, SA, SC, SD, SG, SL, SN, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Molavir (ID); Norum (TH); Oppvir (TH, TW); Opthavir (MX); Ozvir (AU); Poviral (EC); Proviral (AR); Qualiclovir (HK); Quavir (ID); Ranvir (TH); Ranviran (PL); Reclovax (TH); Remex (FR); Skirax (TW); Sophivir Ungena (MX); Supra-Vir (IL); Supraviran (DE, LU, PL); Supraviran Creme (AE, BH, CY, DE, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Syntovir (HK); Telviran (HU); Vacrax (MY); Vacrovir (KP); Vermis (TH); Vicorax (TH, TW); Victoclir (MX); Viracir (PL); Viralex-DS (PH); Viralis (ID); Virax (KP); Virest (MY, SG); Virestat (MX); Virex (CO); Virherpes (ES); Virless (CL, SG, TW); Viroclear (HK); Virogon (TH); Virokill (HU); Virolan (TW); Virolex (HR, HU, PL); Viromed (TH); Virucid (HK); Virules (HK); Vivir (KP); Warviron (HK); Zeven Cream (MY); Zevin (TH); Zirconia (MX); Ziverone (MX); Zodiac (KP); Zoral (HK, SG); Zoral Cream (MY); Zorax (SG); Zoter (ID); Zoteran (PH); Zovir (DK); Zovirax (AE, AR, AT, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BO, BR, BS, BZ, CH, CI, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, HR, HU, ID, IE, IL, IN, IQ, IR, IT, JM, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, OM, PA, PE, PH, PK, PR, PT, PY, QA, RU, SA, SC, SD, SE, SG, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UG, UY, VE, YE, ZA, ZM, ZW); Zovirax [tabs./susp./ungt.] (PL); Zyclorax (ID); Zyvir (KE)
MECHANISM OF ACTION — Acyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.
PHARMACODYNAMICS / KINETICS
Absorption: Oral: 15% to 30%
Distribution: Vd: 0.8 L/kg (63.6 L): Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, CSF)
Protein binding: 9% to 33%
Metabolism: Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes
Bioavailability: Oral: 10% to 20% with normal renal function (bioavailability decreases with increased dose)
Half-life elimination: Terminal: Neonates: 4 hours; Children 1-12 years: 2-3 hours; Adults: 3 hours
Time to peak, serum: Oral: Within 1.5-2 hours
Excretion: Urine (62% to 90% as unchanged drug and metabolite)
PATIENT INFORMATION — This is not a cure for herpes (recurrences tend to continually reappear every 3-6 months after original infection), nor will this medication reduce the risk of transmission to others when lesions are present; avoid sexual intercourse when visible lesions are present. Take as directed for full course of therapy; do not discontinue even if feeling better. Oral doses may be taken with food.
ctivated prothrombin complex concentrates
U.S. BRAND NAMES — Feiba VH
PHARMACOLOGIC CATEGORY
Activated Prothrombin Complex Concentrate (aPCC)
Antihemophilic Agent
Blood Product Derivative
DOSING: ADULTS — Control of bleeding: I.V.:
General dosing guidelines: 50-100 units/kg (maximum 200 units/kg)
Joint hemorrhage: 50 units/kg every 12 hours; may increase to 100 units/kg; continue until signs of clinical improvement occur
Mucous membrane bleeding: 50 units/kg every 6 hours; may increase to 100 units/kg (maximum: 2 administrations/day or 200 units/kg/day)
Soft tissue hemorrhage: 100 units/kg every 12 hours (maximum: 200 units/kg/day)
Other severe hemorrhage: 100 units/kg every 12 hours; may be used every 6 hours if needed; continue until clinical improvement
DOSING: PEDIATRIC — Refer to adult dosing.
(For additional information see "Activated prothrombin complex concentrates (factor VIII inhibitor bypassing activity): Pediatric drug information")
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Feiba VH: Each bottle is labeled with Immuno units of factor VIII [heparin free; contains sodium 8 mg/mL; packaging contains natural rubber latex]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Feiba VH: Each bottle is labeled with Immuno units of factor VIII [heparin free; contains sodium 8 mg/mL]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Maximum infusion rate: 2 units/kg/minute. Following reconstitution, complete infusion within 3 hours.
USE — Hemophilia A & B patients with inhibitors who are to undergo surgery or those who are bleeding
USE - UNLABELED / INVESTIGATIONAL — Nonhemophiliac patients with acquired inhibitors with titers >5 Bethesda units (BU) to factors VIII, XI, and XII
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Blood pressure changes, chest pain, MI, pulse rate changes, thromboembolism
Dermatologic: Rash, urticaria
Hematologic: DIC, fibrin decreased, fibrin split products increased, platelets decreased, PT increased, PTT increased
Respiratory: Cough, respiratory distress
Miscellaneous: Allergic reaction, anamnestic response
CONTRAINDICATIONS — Patients with normal coagulation mechanism
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Thrombotic events: Observe closely for signs and symptoms of intravascular coagulation or thrombosis. High doses have been associated with thrombotic complications, including MI and DIC; single doses should not exceed 100 units/kg and daily doses should not exceed 200 units/kg. Use with caution when administering to patients with liver disease, postoperatively, neonates, or patients at risk of thromboembolic phenomena, disseminated intravascular coagulation or patients with signs of fibrinolysis due to the potential risk of thromboembolic complications.
Disease-related concerns: Hepatic impairment: Use with extreme caution in patients with hepatic impairment.
Dosage form specific issues: Factor VIII: Product contains minute amounts of factor VIII which may cause an anamnestic response. Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer. Latex: Product packaging may contain natural rubber latex.
Other warnings/precautions: Appropriate use: Should only be used to control bleeding in patients with inhibitors resulting from coagulation factor deficiencies. Tests used to control improvement, such as aPTT, whole blood clotting time (WBCT), and thromboelastography (TEG), do not correlate with clinical efficacy. Dosing to normalize these values may result in DIC.
DRUG INTERACTIONS
Antifibrinolytic Agents: May enhance the thrombogenic effect of Anti-inhibitor Coagulant Complex. Risk X: Avoid combination
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Reproduction studies have not been conducted.
LACTATION — Excretion in breast milk unknown/use caution
DIETARY CONSIDERATIONS — Contains sodium 8 mg/mL
MONITORING PARAMETERS — Monitor for control of bleeding; signs and symptoms of DIC (blood pressure changes, pulse rate changes, chest pain/cough, fibrinogen decreased, platelet count decreased, fibrin-fibrinogen degradation products, significantly-prolonged thrombin time, PT, or partial thromboplastin time); hypotension; have epinephrine ready to treat hypersensitivity reactions. Note: Tests used to control efficacy such as aPTT, WBCT, and TEG do not correlate with clinical improvement. Dosing to normalize these values may result in DIC.
CANADIAN BRAND NAMES — Feiba VH Immuno
PHARMACOLOGIC CATEGORY
Activated Prothrombin Complex Concentrate (aPCC)
Antihemophilic Agent
Blood Product Derivative
DOSING: ADULTS — Control of bleeding: I.V.:
General dosing guidelines: 50-100 units/kg (maximum 200 units/kg)
Joint hemorrhage: 50 units/kg every 12 hours; may increase to 100 units/kg; continue until signs of clinical improvement occur
Mucous membrane bleeding: 50 units/kg every 6 hours; may increase to 100 units/kg (maximum: 2 administrations/day or 200 units/kg/day)
Soft tissue hemorrhage: 100 units/kg every 12 hours (maximum: 200 units/kg/day)
Other severe hemorrhage: 100 units/kg every 12 hours; may be used every 6 hours if needed; continue until clinical improvement
DOSING: PEDIATRIC — Refer to adult dosing.
(For additional information see "Activated prothrombin complex concentrates (factor VIII inhibitor bypassing activity): Pediatric drug information")
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Feiba VH: Each bottle is labeled with Immuno units of factor VIII [heparin free; contains sodium 8 mg/mL; packaging contains natural rubber latex]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Feiba VH: Each bottle is labeled with Immuno units of factor VIII [heparin free; contains sodium 8 mg/mL]
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Maximum infusion rate: 2 units/kg/minute. Following reconstitution, complete infusion within 3 hours.
USE — Hemophilia A & B patients with inhibitors who are to undergo surgery or those who are bleeding
USE - UNLABELED / INVESTIGATIONAL — Nonhemophiliac patients with acquired inhibitors with titers >5 Bethesda units (BU) to factors VIII, XI, and XII
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Blood pressure changes, chest pain, MI, pulse rate changes, thromboembolism
Dermatologic: Rash, urticaria
Hematologic: DIC, fibrin decreased, fibrin split products increased, platelets decreased, PT increased, PTT increased
Respiratory: Cough, respiratory distress
Miscellaneous: Allergic reaction, anamnestic response
CONTRAINDICATIONS — Patients with normal coagulation mechanism
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Thrombotic events: Observe closely for signs and symptoms of intravascular coagulation or thrombosis. High doses have been associated with thrombotic complications, including MI and DIC; single doses should not exceed 100 units/kg and daily doses should not exceed 200 units/kg. Use with caution when administering to patients with liver disease, postoperatively, neonates, or patients at risk of thromboembolic phenomena, disseminated intravascular coagulation or patients with signs of fibrinolysis due to the potential risk of thromboembolic complications.
Disease-related concerns: Hepatic impairment: Use with extreme caution in patients with hepatic impairment.
Dosage form specific issues: Factor VIII: Product contains minute amounts of factor VIII which may cause an anamnestic response. Human plasma: Product of human plasma; may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer. Latex: Product packaging may contain natural rubber latex.
Other warnings/precautions: Appropriate use: Should only be used to control bleeding in patients with inhibitors resulting from coagulation factor deficiencies. Tests used to control improvement, such as aPTT, whole blood clotting time (WBCT), and thromboelastography (TEG), do not correlate with clinical efficacy. Dosing to normalize these values may result in DIC.
DRUG INTERACTIONS
Antifibrinolytic Agents: May enhance the thrombogenic effect of Anti-inhibitor Coagulant Complex. Risk X: Avoid combination
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Reproduction studies have not been conducted.
LACTATION — Excretion in breast milk unknown/use caution
DIETARY CONSIDERATIONS — Contains sodium 8 mg/mL
MONITORING PARAMETERS — Monitor for control of bleeding; signs and symptoms of DIC (blood pressure changes, pulse rate changes, chest pain/cough, fibrinogen decreased, platelet count decreased, fibrin-fibrinogen degradation products, significantly-prolonged thrombin time, PT, or partial thromboplastin time); hypotension; have epinephrine ready to treat hypersensitivity reactions. Note: Tests used to control efficacy such as aPTT, WBCT, and TEG do not correlate with clinical improvement. Dosing to normalize these values may result in DIC.
CANADIAN BRAND NAMES — Feiba VH Immuno
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