Acyclovir Sodium

Class: Nucleosides and Nucleotides
VA Class: AM800
CAS Number: 59277-89-3
Brands: Zovirax

Introduction

Antiviral; purine nucleoside analog derived from guanine.^{403 409}

Uses for Acyclovir Sodium

Mucocutaneous, Ocular, and Systemic Herpes Simplex Virus (HSV) Infections

Treatment of initial and recurrent mucocutaneous HSV-1 and HSV-2 infections (e.g., orofacial, esophageal, genital, nasal, labial) in immunocompromised adults, adolescents, and children, including HIV-infected individuals.^{322 381 396 409 410 412 413} Drug of choice.^{322 381 396 410 412 413}

Chronic suppressive or maintenance therapy (secondary prophylaxis) of recurrent HSV infections† in immunocompromised adults, adolescents, and children, including HIV-infected individuals who have frequent or severe recurrences.^{322 392 404 412}

Treatment of orolabial HSV infections (including gingivostomatitis) in immunocompetent† adults and children;^{322 381 418} generally ineffective or minimally effective for prevention of recurrence of herpes labialis† in immunocompetent individuals.^{322 422}

Treatment of eczema herpeticum† in patients with a history of atopic dermatitis.^{223 224}

Treatment of HSV keratitis† in HIV-infected patients.⁴⁰⁷

Prophylaxis against recurrence of ocular HSV disease† in immunocompetent adults and children ≥12 years of age who had ocular HSV disease (blepharitis, conjunctivitis, epithelial keratitis, stromal keratitis, iritis) in one or both eyes within the preceding 12 months.^{408 419} Has been used for prophylaxis after penetrating keratoplasty for herpetic keratitis.⁴²⁰

Drug of choice for treatment of HSV encephalitis.^{211 212 246 248 322 381 395 409 410 412 413}

Drug of choice for treatment of neonatal HSV infections, including mucocutaneous infections, infections involving skin, eyes, and mouth, and disseminated or CNS infections.^{244 322 324 353 356 381 395 408 409 410 413}

Drug of choice for prevention of HSV recurrence† in hematopoietic stem cell transplant (HSCT) recipients seropositive for HSV; such prophylaxis not indicated in those seronegative for HSV.⁴¹⁴

Genital Herpes

Treatment of initial episodes of genital herpes in adults and adolescents,^{206 207 208 244 305 313 322 381 403 409} including HIV-infected individuals.⁴¹²

Treatment of first episodes of herpes proctitis†.³⁰⁵

Episodic treatment of recurrent episodes of genital herpes in adults and adolescents,^{244 313 322 381 403} including HIV-infected individuals.^{244 412}

Chronic suppressive therapy of recurrent episodes of genital herpes in adults and adolescents,^{202 203 210 242 244 313 317 318 319 320 321 322 381 384 386 403} including HIV-infected individuals.^{244 412}

CDC and others recommend oral acyclovir, oral famciclovir, or oral valacyclovir as drugs of choice for treatment of initial episodes of genital herpes and for episodic treatment or chronic suppressive therapy of recurrent genital herpes.^{244 313 381 412}

Varicella-Zoster Infections

Treatment of varicella (chickenpox) in immunocompromised adults, adolescents, and children, including HIV-infected individuals.^{249 277 279 322 352 353 368 403 409 410 412 413} Drug of choice.^{249 277 279 322 352 353 368 410 412 413}

Treatment of varicella (chickenpox) in immunocompetent adults, adolescents, and children.^{239 322 337 338 340 344 348 352 353 368 381 394 403 410 415} Varicella usually is a self-limited disease in otherwise healthy individuals and the role of acyclovir for treatment in these individuals is controversial;^{239 329 330 331 332 333 335 336 337 338 344 349 350 355 368} routine use not recommended by AAP and other clinicians.^{322 331 332 335 344 345 368}

Treatment of herpes zoster (shingles, zoster) in immunocompetent^{261 284 285 309 353} or immunocompromised adults, adolescents, and children, including HIV-infected individuals.^{322 358 359 381 403 409 410 412 413} Drug of choice for serious or disseminated herpes zoster in immunocompromised patients.^{381 413}

Treatment of herpes zoster ophthalmicus† in HIV-infected patients.^{407 412}

Treatment of dermatomal herpes zoster in immunocompromised patients† including transplant recipients²²⁵ and HIV-infected patients.^{219 407 412}

Alternative to varicella-zoster immune globulin (VZIG) for postexposure prophylaxis of VZV infection† in HSCT recipients.⁴¹⁴ Although long-term prophylaxis not routinely recommended for prevention of recurrent VZV infections in HSCT recipients, such prophylaxis may be considered in those with severe, long-term immunodeficiency.⁴¹⁴

Prevention of Cytomegalovirus (CMV) Disease in Transplant Recipients

Has been used for prevention of CMV disease† in solid organ transplant recipients^{354 360 363 364 365 366 367 398 399 414} and bone marrow transplant (BMT) recipients at risk for the disease; data regarding efficacy are conflicting.^{354 360 365 367 382}

Has been used for prevention of CMV disease† in HSCT recipients; generally ineffective after autologous HSCT.⁴¹⁴ Ganciclovir is drug of choice for prevention of CMV following autologous or allogeneic HSCT in adults, adolescents, and children.⁴¹⁴

Not effective for prevention of CMV disease in HIV-infected individuals.⁴⁰⁴

Epstein-Barr Virus Infections and Disorders

Treatment of uncomplicated or complicated infectious mononucleosis, chronic infectious mononucleosis, and various disorders (e.g., oral hairy leukoplakia) associated with Epstein-Barr virus infections†;^{262 270 271 272 369 396} efficacy appears to be variable.^{230 262 272 273 274 275 276 369}

Acyclovir Sodium Dosage and Administration

Administration

Administer orally or by IV infusion.^{403 409}

Parenteral preparation should not be administered orally or by IM or sub-Q injection and should not be applied topically or to the eye.⁴⁰⁹

Oral Administration

Administer without regard to meals.^{213 403}

IV Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute vial containing 500 mg or 1 g of acyclovir powder with 10 or 20 mL of sterile water for injection, respectively, to provide a solution containing 50 mg/mL.⁴⁰⁹

Shake well to ensure complete dissolution.⁴⁰⁹ Must be diluted further before IV administration.⁴⁰⁹

Dilution

For IV infusion, dilute concentrate containing acyclovir 25 or 50 mg/mL with a compatible IV solution (see Solution Compatibility under Stability) to a concentration of ≤7 mg/mL.⁴⁰⁹

Alternatively, dilute solutions reconstituted from powder prior to IV infusion with 50–125 mL of a compatible IV infusion solution.⁴⁰⁹ (See Solution Compatibility under Stability.) For fluid-restricted patients, dilute reconstituted solution in a ratio of approximately 1 part reconstituted solution to 9 parts infusion solution to a concentration of ≤7 mg/mL.⁴⁰⁹

Rate of Administration

Administer by IV infusion at a constant rate over at least 1 hour.⁴⁰⁹ Do not administer by rapid IV infusion (over <10 minutes) or rapid IV injection.⁴⁰⁹ (See Renal Effects under Cautions.)

Ensure adequate hydration.⁴⁰⁹

Dosage

Available as acyclovir and acyclovir sodium; dosage expressed in terms of acyclovir.⁴⁰⁹

Pediatric Patients

Mucocutaneous, Ocular, and Systemic Herpes Simplex Virus (HSV) Infections

Treatment of Mucocutaneous HSV Infections

Oral†

Immunocompromised children: 1 g daily given in 3–5 divided doses for 7–14 days.³²²

IV

Immunocompromised children <12 years of age: 10 mg/kg every 8 hours for 7–14 days.^{322 381 409}

HIV-infected or immunocompromised adolescents and children ≥12 years of age: 5 mg/kg every 8 hours for 7–14 days.^{322 381 409 412} Alternatively, after lesions begin to regress, consider switching to oral acyclovir in a dosage of 400 mg 3 times daily and continue until lesions are completely healed.⁴¹²

HSV Gingivostomatitis

Oral†

HIV-infected children with mild, symptomatic gingivostomatitis: CDC and others recommend 20 mg/kg (up to 400 mg) 3 times daily for 7–14 days.⁴¹³

Immunocompetent children: 15 mg/kg (up to 200 mg) 5 times daily for 7 days has been used in a few children 1–6 years of age.⁴¹⁸

IV

HIV-infected children with moderate to severe gingivostomatitis: CDC and others recommend 5–10 mg/kg 3 times daily for 7–14 days.⁴¹³ Consider chronic oral suppressive or maintenance therapy (secondary prophylaxis) in those with frequent or severe recurrences of gingivostomatitis.⁴¹³

Chronic Suppressive or Maintenance Therapy (Secondary Prophylaxis) of HSV Infections†

Oral

HIV-infected infants and children: 80 mg/kg daily (up to 1 g daily) in 3 or 4 divided doses.⁴⁰⁴

HIV-infected adolescents: 200 mg 3 times daily or 400 mg twice daily.⁴⁰⁴

Prophylaxis Against Recurrent Ocular HSV Disease†

Oral

Children ≥12 years of age: 400 mg twice daily.^{408 419} AAP recommends 80 mg/kg daily (up to 1 g daily) given in 3 divided doses.³²²

Optimum duration of prophylaxis unclear;⁴¹⁹ has been continued for 12–18 months in clinical studies.^{408 419}

Treatment of HSV Encephalitis or Disseminated Disease

IV

Immunocompromised children: 20 mg/kg every 8 hours in those 3 months to 12 years of age^{381 409} and 10–15 mg/kg every 8 hours in those ≥12 years of age.^{211 246 322 409 413} Manufacturer recommends a treatment duration of 10 days,⁴⁰⁹ but AAP and others recommend 14–21 days for disseminated or CNS infections.^{235 236 311 322 381 413}

HIV-infected children: CDC and others recommend 10 mg/kg or 500 mg/m² 3 times daily for 21 days.⁴¹³

HIV-infected adolescents: CDC and others recommend 10 mg/kg 3 times daily for 14–21 days.⁴¹²

Treatment of Neonatal HSV Infections

IV

Neonates and children ≤3 months of age: Manufacturer recommends 10 mg/kg every 8 hours for 10 days.⁴⁰⁹

Neonates and children ≤3 months of age: AAP recommends 20 mg/kg every 8 hours given for 14 days for infections of skin, eyes, or mouth or 21 days for disseminated or CNS infections.³²²

HIV-infected or -exposed neonates: CDC and others recommend 20 mg/kg 3 times daily given for 14 days for infections of skin, eyes, or mouth or 21 days for disseminated or CNS infections.⁴¹³

Prevention of HSV Recurrence in Hematopoietic Stem Cell Transplant (HSCT) Recipients†

Oral

HSV-seropositive children: 0.6–1 g daily given in 3–5 divided doses.⁴¹⁴

HSV-seropositive adolescents: 200 mg 3 times daily.⁴¹⁴

Initiate prophylaxis at beginning of conditioning therapy and continue until engraftment or until mucositis resolves (approximately 30 days after allogeneic HSCT).⁴¹⁴ Routine prophylaxis for >30 days after HSCT not recommended.⁴¹⁴

IV

HSV-seropositive children: 250 mg/m² every 8 hours or 125 mg/m² every 6 hours.⁴¹⁴

HSV-seropositive adolescents: 250 mg/m² every 12 hours.

Initiate prophylaxis at beginning of conditioning therapy and continue until engraftment or until mucositis resolves (approximately 30 days after allogeneic HSCT).⁴¹⁴ Routine prophylaxis for >30 days after HSCT not recommended.⁴¹⁴

Genital Herpes

Treatment of First Episodes

Oral

Children: AAP recommends 40–80 mg/kg daily (maximum 1 g daily) given in 3 or 4 divided doses for 5–10 days.³²²

Adolescents: CDC recommends 400 mg 3 times daily or 200 mg 5 times daily for 7–10 days;²⁴⁴ duration may be extended if healing is incomplete after 10 days.²⁴⁴

HIV-infected adolescents: CDC and others recommend 20 mg/kg (up to 400 mg) or 400 mg 3 times daily for 7–14 days.⁴¹²

IV

Adolescents and children ≥12 years of age with severe initial episodes: 5–10 mg/kg every 8 hours.^{244 381 409 410}

Manufacturer and some clinicians recommend 5–7 days of IV acyclovir;^{381 409} CDC states IV acyclovir should be given for 2–7 days or until clinical improvement occurs, followed by an oral antiviral to complete at least 10 days of treatment.²⁴⁴

Episodic Treatment of Recurrent Episodes

Oral

Adolescents: CDC recommends 400 mg 3 times daily for 5 days, 800 mg twice daily for 5 days, or 800 mg 3 times daily for 2 days.²⁴⁴

HIV-infected adolescents: CDC recommends 400 mg 3 times daily for 5–10 days.²⁴⁴ Alternatively, acyclovir can be given for 7–14 days.⁴¹²

Initiate episodic therapy at the earliest prodromal sign or symptom of recurrence or within 1 day of the onset of lesions.^{244 403}

Chronic Suppression of Recurrent Episodes

Oral

Adolescents: CDC recommends 400 mg twice daily.²⁴⁴

HIV-infected adolescents: CDC recommends 400–800 mg 2 or 3 times daily.²⁴⁴

Discontinue periodically (e.g., after 12 months or once yearly) to reassess need for continued therapy.^{244 403}

Varicella-Zoster Infections

Treatment of Varicella (Chickenpox)

Oral

Immunocompetent children ≥2 years of age: Manufacturer recommends 20 mg/kg 4 times daily (maximum 80 mg/kg daily) for 5 days in those weighing ≤40 kg and 800 mg 4 times daily for 5 days in those weighing >40 kg.⁴⁰³ Alternatively, some clinicians recommend 20 mg/kg (up to 800 mg) 4 times daily for 5 days.^{239 322 329 331 336 368 381 410}

HIV-infected children with mild immunosuppression and mild varicella: CDC and others recommend 20 mg/kg (up to 800 mg) 4 times daily for 7 days or until no new lesions have appeared for 48 hours.⁴¹³

Initiate therapy at the earliest sign or symptom of infection (within 24 hours of onset of rash).^{368 403}

IV

Immunocompromised children: AAP recommends 10 mg/kg 3 times daily for 7–10 days for those <1 year of age and 500 mg/m² 3 times daily for 7–10 days in those ≥1 year of age.³²²

Immunocompromised adolescents and children: Some clinicians recommend 20 mg/kg every 8 hours for 7–10 days in those ≤12 years of age and 10 mg/kg every 8 hours for 7 days in those >12 years of age.³⁸¹

HIV-infected children with moderate or severe immunosuppression and varicella associated with high fever or necrotic lesions: CDC and others recommend 10 mg/kg 3 times daily for 7 days or until no new lesions have appeared for 48 hours.⁴¹³ Alternatively, a dosage of 500 mg/m² every 8 hours has been suggested for those ≥1 year of age.⁴¹³

HIV-infected adolescents: CDC and others recommend 10 mg/kg every 8 hours for 7–10 days.⁴¹² After defervescence and if there is no evidence of visceral involvement, switch to oral acyclovir in a dosage of 800 mg 4 times daily.⁴¹²

Treatment of Herpes Zoster (Shingles, Zoster)

Oral

Immunocompetent children ≥12 years of age: 800 mg every 4 hours 5 times daily (4 g daily) for 5–10 days.^{261 284 285 309 322 381 403 410}

HIV-infected children with mild immunosuppression and mild varicella: CDC and others recommend 20 mg/kg (up to 800 mg) 4 times daily for 7–10 days.⁴¹³

Initiate therapy preferably within 48 hours of onset of rash.^{261 284 285 309 322 381 403 410}

IV

Immunocompetent children: AAP recommends 10 mg/kg 3 times daily for 7–10 days for those <1 year of age and 500 mg/m² 3 times daily for 7–10 days in those ≥1 year of age.³²²

Immunocompromised children: 20 mg/kg every 8 hours for 7–10 days in those <12 years of age^{381 322 409 413} and 10 mg/kg every 8 hours for 7 days in those ≥12 years of age.^{381 409 410}

HIV-infected children with severe immunosuppression and extensive multidermatomal zoster or zoster with trigeminal nerve involvement: CDC and others recommend 10 mg/kg 3 times daily for 7–10 days.⁴¹³

HIV-infected adolescents: CDC and others recommend 10 mg/kg every 8 hours until cutaneous and visceral disease resolves.⁴¹²

Adults

Mucocutaneous, Ocular, and Systemic Herpes Simplex Virus (HSV) Infections

Treatment of Mucocutaneous HSV Infections

Oral†

Immunocompromised or HIV-infected adults: 400 mg every 4 hours while awake (5 times daily) for 7–14 days.^{381 410}

IV

Immunocompromised or HIV-infected adults: CDC and others recommend 5 mg/kg every 8 hours for 7–14 days.^{381 409 412} Alternatively, after lesions begin to regress, consider switching to oral acyclovir in a dosage of 400 mg 3 times daily and continue until lesions are completely healed.⁴¹²

Chronic Suppressive or Maintenance Therapy (Secondary Prophylaxis) of HSV Infections†

Oral

HIV-infected adults: 200 mg 3 times daily or 400 mg twice daily.⁴⁰⁴

Treatment of Orolabial HSV Infections

Oral

400 mg 5 times daily for 5 days.³⁸¹

HIV-infected adults: CDC and others recommend 400 mg 3 times daily for 7–14 days.^{381 412}

Treatment of HSV Keratitis†

Oral

HIV-infected adults: 400 mg 5 times daily.⁴⁰⁷ Long-term therapy may be required to prevent recurrence.⁴⁰⁷

Prophylaxis Against Recurrent Ocular HSV Disease†

Oral

Immunocompetent adults: 400 mg twice daily.^{408 419 420} Optimum duration of prophylaxis unclear;⁴¹⁹ has been continued for 12–18 months in clinical studies.^{408 419}

Treatment of HSV Encephalitis or Disseminated Disease

IV

10–15 mg/kg every 8 hours.^{211 246 322 381 409 412} Manufacturer recommends a treatment duration of 10 days,⁴⁰⁹ but CDC and others recommend 14–21 days for disseminated or CNS infections.^{235 236 311 381 412}

HIV-infected adults: CDC and others recommend 10 mg/kg 3 times daily for 14–21 days.⁴¹²

Prevention of HSV Recurrence in Hematopoietic Stem Cell Transplant (HSCT) Recipients†

Oral

HSV-seropositive adults: 200 mg 3 times daily initiated at beginning of conditioning therapy and continued until engraftment or until mucositis resolves (i.e., approximately 30 days after allogeneic HSCT).⁴¹⁴ Routine prophylaxis for >30 days after HSCT not recommended.⁴¹⁴

IV

HSV-seropositive adults: 250 mg/m² every 12 hours initiated at beginning of conditioning therapy and continued until engraftment or until mucositis resolves (i.e., approximately 30 days after allogeneic HSCT).⁴¹⁴ Routine prophylaxis for >30 days after HSCT not recommended.⁴¹⁴

Genital Herpes

Treatment of First Episodes

Oral

Manufacturer recommends 200 mg every 4 hours while awake (5 times daily) for 10 days.⁴⁰³

CDC and others recommend 400 mg 3 times daily or 200 mg 5 times daily for 7–10 days;^{244 313 381 410} duration may be extended if healing is incomplete after 10 days.²⁴⁴

HIV-infected adults: CDC and others recommend 400 mg 3 times daily for 7–14 days.⁴¹²

IV

Adults with severe initial episodes: 5–10 mg/kg every 8 hours.^{244 313 381 409 410}

Manufacturer and some clinicians recommend 5–7 days of IV acyclovir;^{313 381 409} CDC states IV acyclovir should be given for 2–7 days or until clinical improvement occurs, followed by an oral antiviral to complete at least 10 days of therapy.²⁴⁴

Treatment of First Episode of Herpes Proctitis†

Oral

400 mg 5 times daily for 10 days or until clinical resolution occurs.³⁰⁵

Episodic Treatment of Recurrent Episodes of Genital Herpes

Oral

Manufacturer recommends 200 mg every 4 hours while awake (5 times daily) for 5 days.⁴⁰³

CDC recommends 400 mg 3 times daily for 5 days, 800 mg twice daily for 5 days, or 800 mg 3 times daily for 2 days.²⁴⁴

HIV-infected adults: CDC recommends 400 mg 3 times daily for 5–10 days.²⁴⁴ Alternatively, acyclovir can be given for 7–14 days.⁴¹²

Initiate episodic therapy at the earliest prodromal sign or symptom of recurrence or within 1 day of the onset of lesions.^{244 403 410}

Chronic Suppression of Recurrent Episodes of Genital Herpes

Oral

400 mg twice daily;^{244 313 381 403} alternatively, 200 mg 3–5 times daily.⁴⁰³

HIV-infected adults: 400–800 mg 2 or 3 times daily.²⁴⁴

Discontinue periodically (e.g., after 12 months or once yearly) to reassess need for continued therapy.^{244 403}

Varicella-Zoster Infections

Treatment of Varicella (Chickenpox)

Oral

20 mg/kg (up to 800 mg) 4 times daily for 5 days.^{239 322 329 331 336 353 368 381 403 410 412}

Initiate therapy at the earliest sign or symptom of infection (within 24 hours of onset of rash).^{368 403}

IV, then Oral

HIV-infected or immunocompromised adults: CDC and others recommend 10 mg/kg every 8 hours for 7–10 days.^{381 412} After defervescence and if there is no evidence of visceral involvement, switch to oral acyclovir in a dosage of 800 mg 4 times daily.⁴¹²

Treatment of Herpes Zoster (Shingles, Zoster)

Oral

800 mg every 4 hours (5 times daily) for 7–10 days.^{261 284 285 309 322 381 403 410}

Initiate therapy preferably within 48 hours of onset of rash.^{261 284 285 309 322 381 410}

IV

HIV-infected or immunocompromised adults: CDC and others recommend 10 mg/kg every 8 hours for 7 days or until cutaneous and visceral disease resolves.^{381 409 410 412}

Treatment of Herpes Zoster Ophthalmicus†

Oral

Immunocompetent adults: 600 mg every 4 hours 5 times daily (3 g daily) for 10 days.^{281 282 286}

Initiate therapy within 72 hours (but no later than 7 days) after rash onset.^{281 282 286}

IV, then Oral

HIV-infected adults: 10 mg/kg IV 3 times daily for 7 days followed by 800 mg orally 3–5 times daily has been used.⁴⁰⁷

Treatment of Dermatomal Herpes Zoster†

Oral

Immunocompromised adults: 800 mg 5 times daily for 10 days has been used,^{219 225} but CDC and others recommend oral famciclovir or valacyclovir for localized dermal infections in HIV-infected individuals.⁴¹²

Prescribing Limits

Pediatric Patients

Oral:

Maximum 20 mg/kg 4 times daily (1 g daily)^{322 403} in children ≥2 years of age weighing ≤40 kg.⁴⁰³

IV:

Maximum 20 mg/kg every 8 hours.⁴⁰⁹

Adults

Oral:

800 mg per dose.^{239 322 329 331 336 353 368 381 410}

IV:

Maximum 20 mg/kg every 8 hours.⁴⁰⁹

Special Populations

Renal Impairment

Adjustment of Usual Oral Dosage

Oral Dosage in Renal Impairment403

Usual Dosage Regimen	Clcr (mL/min per 1.73 m2)	Adjusted Dosage Regimen
200 mg every 4 h 5 times daily	>10	No adjustment necessary
	0–10	200 mg every 12 h
400 mg every 12 h	>10	No adjustment necessary
	0–10	200 mg every 12 h
800 mg every 4 h 5 times daily	>25	No adjustment necessary
	10–25	800 mg every 8 h
	0–10	800 mg every 12 h

Hemodialysis

Give supplemental oral dose immediately after each dialysis period.⁴⁰³

Peritoneal Dialysis

Supplemental doses do not appear necessary.⁴⁰³

Adjustment of Usual IV Dosage

IV Dosage in Renal Impairment409

Clcr (mL/min per 1.73 m2)	Percent of Recommended Dose	Dosing Interval (hours)
>50	100%	8
25–50	100%	12
10–25	100%	24
0–10	50%	24

Hemodialysis

Adjust dosing schedule so that a supplemental IV dose is administered immediately after each dialysis period.⁴⁰⁹

CAPD

Supplemental doses do not appear necessary.³¹⁶

Alternative IV Dosage Regimens for End-Stage Renal Disease

93–185 mg/m² as a loading dose, followed by a maintenance dosage of 35–70 mg/m² every 8 hours, and 56–185 mg/m² immediately after dialysis.^a

250–500 mg/m² as a loading dose, followed by a maintenance dosage of 250–500 mg/m² every 48 hours, and 150–500 mg/m² immediately after dialysis.^a

2.5 mg/kg every 24 hours and 2.5 mg/kg after each dialysis period.^a

HIV-infected Patients with Impaired Renal Function (Oral Administration)

Oral Dosage for HIV-infected Patients with Impaired Renal Function (Based on Usual Dosage of 200–800 mg Every 4–6 Hours)411

Clcr (mL/min per 1.73 m2)	Adjusted Dosage Regimen
>80	No adjustment necessary
50–80	200–800 mg every 6–8 h
25–50	200–800 mg every 8–12 h
10–25	200–800 mg every 12–24 h
<10	200–400 mg every 24 h

Hemodialysis

Give supplemental usual oral dose after each dialysis period.⁴¹¹

HIV-infected Patients with Impaired Renal Function (IV Administration)

IV Dosage for HIV-infected Patients with Impaired Renal Function (Based on Usual Dosage of 5 mg/kg Every 8 hours)409411

Clcr (mL/min per 1.73 m2)	Adjusted Dosage Regimen
>80	No adjustment necessary
50–80	No adjustment necessary
25–50	5 mg/kg every 12–24 hours
10–25	5 mg/kg every 12–24 hours
<10	2.5 mg/kg every 24 hours

Hemodialysis

Adjust dosing schedule so that daily IV dose is given after hemodialysis on dialysis days.⁴¹¹

Geriatric Patients

Cautious dosage selection; reduced dosage may be needed because of age-related decreases in renal function.^{403 409} (See Geriatric Use under Cautions.)

Obese Patients

Use ideal body weight to determine IV dosage.⁴⁰⁹

Cautions for Acyclovir Sodium

Contraindications

• 
  

  Known hypersensitivity to acyclovir or valacyclovir.^{403 409}

  
  

Warnings/Precautions

Warnings

Renal Effects

Increased BUN and/or S_cr, anuria, and hematuria have been reported.^{403 409} Transient increases in BUN and/or S_cr and decreases in Cl_cr reported in patients receiving IV acyclovir, particularly following rapid (over <10 minutes) IV infusion.⁴⁰⁹

Abnormal urinalysis (increase in formed elements in urine sediment) and pain or pressure on urination reported rarely with IV acyclovir.⁴⁰⁹

Renal failure, resulting in death, has occurred.^{341 403 409}

Possible precipitation of acyclovir in renal tubules, resulting in renal tubular damage and acute renal failure, when the solubility of free acyclovir in the collecting duct is exceeded or following rapid IV administration.⁴⁰⁹

Risk of adverse renal effects during IV therapy depends on degree of hydration, urine output, concomitant therapy (i.e., nephrotoxic drugs), preexisting renal disease, and rate of administration (see Rate of Administration under Dosage and Administration).⁴⁰⁹

Alterations in renal function during IV acyclovir therapy can progress to acute renal failure but generally are transient and resolve spontaneously or following improved hydration and electrolyte balance, dosage adjustment, or discontinuance of the drug.⁴⁰⁹

Hematologic Effects

Potentially fatal thrombotic thrombocytopenic purpura/hemolytic uremic syndrome reported in immunocompromised patients receiving acyclovir.^{403 409}

General Precautions

Nervous System Effects

Possible encephalopathic effects (e.g., lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, coma) in patients receiving IV acyclovir.⁴⁰⁹

Use with caution in patients with underlying neurologic abnormalities and in those with serious renal, hepatic, or electrolyte abnormalities or substantial hypoxia.⁴⁰⁹

Local Effects

Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of acyclovir into extravascular tissues.⁴⁰⁹

Sodium Content

Sodium salt of acyclovir contains 4.2 mEq of sodium per gram of acyclovir.⁴⁰⁹

Specific Populations

Pregnancy

Category B.^{403 409}

CDC, AAP, and others state that oral acyclovir may be used during pregnancy to treat first episodes or severe recurrent episodes of genital herpes^{244 322 381 412 421} and IV acyclovir may be used during pregnancy to treat severe HSV infection (especially life-threatening disseminated infections).^{244 322 412 421} CDC and others also recommend acyclovir for treatment of varicella during pregnancy,^{412 415} particularly during the second and third trimesters.⁴¹⁵

Lactation

Distributed into milk following oral or IV administration.^{251 308 403 409 421} Use with caution.^{403 409}

Women with active herpetic lesions near or on the breast should refrain from breast-feeding.³²²

Pediatric Use

Safety and efficacy of oral acyclovir not established in children <2 years of age.⁴⁰³

Geriatric Use

For treatment of herpes zoster (shingles, zoster), no substantial differences in efficacy of oral acyclovir relative to younger adults, but duration of pain after healing may be longer in geriatric patients.⁴⁰³

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently to IV acyclovir than younger adults.⁴⁰⁹

Select dosage with caution because of age-related decreases in renal function and potential for concomitant disease and drug therapy.⁴⁰⁹ Consider monitoring renal function.⁴⁰⁹

Possible increased incidence of adverse CNS effects (coma, confusion, hallucinations, somnolence), GI effects (nausea, vomiting), or dizziness during oral acyclovir therapy compared with younger adults.⁴⁰³

Hepatic Impairment

Use with caution.^a

Renal Impairment

Huma-Folacid

Huma-Folacid may be available in the countries listed below.

Ingredient matches for Huma-Folacid

Folic Acid

Folic Acid is reported as an ingredient of Huma-Folacid in the following countries:

• Hungary

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Calcium Folinate Hospira

Calcium Folinate Hospira may be available in the countries listed below.

Ingredient matches for Calcium Folinate Hospira

Calcium Folinate

Calcium Folinate is reported as an ingredient of Calcium Folinate Hospira in the following countries:

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Doc Captopri may be available in the countries listed below.

Ingredient matches for Doc Captopri

Captopril

Captopril is reported as an ingredient of Doc Captopri in the following countries:

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L-Polamivet

L-Polamivet may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for L-Polamivet

Fenpipramide

Fenpipramide hydrochloride (a derivative of Fenpipramide) is reported as an ingredient of L-Polamivet in the following countries:

• Finland


• Germany


• Switzerland

Levomethadone

Levomethadone hydrochloride (a derivative of Levomethadone) is reported as an ingredient of L-Polamivet in the following countries:

• Finland


• Germany


• Switzerland

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Mithracin

Generic Name: plicamycin (plih CA my sin)

Brand Names: Mithracin

What is Mithracin (plicamycin)?

Plicamycin is a cancer (antineoplastic) medication. Plicamycin interferes with the growth of cancer cells and slows their growth and spread in the body.

Plicamycin is used to treat cancer of the testicles. Plicamycin is also used in the treatment of treat too much calcium in the blood (hypercalcemia) and too much calcium in the urine (hypercalciuria) associated with a variety of advanced forms of cancer.

Plicamycin may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Mithracin (plicamycin)?

Plicamycin should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Serious side effects have been reported with the use of plicamycin including: allergic reactions (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; fever or chills; or signs of infection such as fever; chills, or sore throat); severe nausea, vomiting, diarrhea, and loss of appetite; and others. Talk to your doctor about the possible side effects from treatment with plicamycin.

Plicamycin should not be used in women who are or may become pregnant.

Who should not take Mithracin (plicamycin)?

Before taking plicamycin, tell your doctor if you have

• liver disease;


• kidney disease;


• 
  

  bone marrow problems; or

  
  


• 
  

  a bleeding disorder.

  
  

You may not be able to take plicamycin, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Plicamycin is in the FDA pregnancy category X. This means that plicamycin is known to cause birth defects in an unborn baby. Plicamycin may also affect egg production in women and sperm production in men. Do not take plicamycin if you are pregnant or could become pregnant during treatment. Contraceptive measures are recommended during treatment with plicamycin. It is not known whether plicamycin passes into breast milk. Do not take plicamycin without first talking to your doctor if you are breast feeding a baby.

How should I take Mithracin (plicamycin)?

Plicamycin should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Your doctor will determine the correct amount and frequency of treatment with plicamycin depending upon the type of cancer being treated and other factors. Talk to your doctor if you have any questions or concerns regarding the treatment schedule.

Your doctor will probably want you to have regularly scheduled blood tests and other medical evaluations during treatment with plicamycin to monitor progress and side effects.

Your healthcare provider will store cladribine as directed by the manufacturer. If you are storing cladribine, follow the directions provided by your healthcare provider.

What happens if I miss a dose?

Contact your doctor if you miss a dose of plicamycin injection.

What happens if I overdose?

If for any reason an overdose of plicamycin is suspected, seek emergency medical attention or contact your healthcare provider immediately.

Symptoms of a plicamycin overdose tend to be similar to side effects caused by the medication, although often more severe.

What should I avoid while taking Mithracin (plicamycin)?

Plicamycin can lower the activity of your immune system making you susceptible to infections. Avoid contact with people who have colds, the flu, or other contagious illnesses and do not receive vaccines that contain live strains of a virus (e.g., live oral polio vaccine) during treatment with plicamycin. In addition, avoid contact with individuals who have recently been vaccinated with a live vaccine. There is a chance that the virus can be passed on to you.

Mithracin (plicamycin) side effects

If you experience any of the following serious side effects, seek emergency medical attention or contact your doctor immediately:

• 
  

  an allergic reaction (shortness of breath; closing of your throat; difficulty breathing; swelling of your lips, face, or tongue; or hives);

  
  


• 
  

  blood in the urine;

  
  


• 
  

  black or tarry stools;

  
  


• 
  

  signs of infection such as fever; chills, or sore throat;

  
  


• 
  

  nose bleed (epistaxis) or vomiting blood (hematemesis); or

  
  


• 
  

  unusual bleeding or bruising.

  
  

Other less serious side effects may be more likely to occur. Talk to your doctor if you experience:

• 
  

  nausea, vomiting, diarrhea, or decreased appetite;

  
  


• 
  

  mouth sores;

  
  


• 
  

  drowsiness and extremely deep sleep;

  
  


• 
  

  a general discomfort or uneasiness;

  
  


• 
  

  headache or depression;

  
  


• 
  

  a rash; or

  
  


• 
  

  facial flushing..

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Mithracin (plicamycin)?

Do not receive "live" vaccines during treatment with plicamycin. Administration of a live vaccine may be dangerous during treatment with plicamycin.

Other drugs may interact with plicamycin. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medicines, including herbal products, during treatment with plicamycin.

More Mithracin resources

• Mithracin Side Effects (in more detail)
• Mithracin Use in Pregnancy & Breastfeeding
• Mithracin Drug Interactions
• Mithracin Support Group
• 0 Reviews for Mithracin - Add your own review/rating

• plicamycin Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Mithracin with other medications

• Hypercalcemia
• Hypercalciuria
• Testicular Cancer

Where can I get more information?

• Your pharmacist has additional information about plicamycin written for health professionals that you may read.

What does my medication look like?

Plicamycin is available with a prescription under the brand name Mithracin. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

See also: Mithracin side effects (in more detail)

Procyclidine

In the US, Procyclidine (procyclidine systemic) is a member of the drug class anticholinergic antiparkinson agents and is used to treat Parkinson's Disease, Parkinsonian Tremor and Parkinsonism.

US matches:

• Procyclidine


• Procyclidine Hydrochloride

Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

N04AA04

CAS registry number (Chemical Abstracts Service)

0000077-37-2

Chemical Formula

C19-H29-N-O

Molecular Weight

287

Therapeutic Category

Treatment of Parkinson's disease: Central anticholinergic

Chemical Name

1-Pyrrolidinepropanol, α-cyclohexyl-α-phenyl-

Foreign Names

• Procyclidinum (Latin)
• Procyclidin (German)
• Procyclidine (French)
• Prociclidina (Spanish)

Generic Names

• Prociclidina (OS: DCIT)
• Procyclidine (OS: BAN, DCF, USAN)
• Procyclidine Hydrochloride (OS: BANM)
• Procyclidine Hydrochloride (PH: USP 32, BP 2010)
• Procyclidini Hydrochloridum (PH: Ph. Int. 2)

Brand Names

• Arpicolin
  Rosemont, United Kingdom



• Extranil
  General Pharma, Bangladesh



• Kdrine
  Opsonin, Bangladesh



• Kemadren
  Glaxo SmithKline, Spain



• Kemadrin
  GlaxoSmithKline, United Arab Emirates; GlaxoSmithKline, Austria; GlaxoSmithKline, Bangladesh; GlaxoSmithKline, Belgium; GlaxoSmithKline, Bahrain; GlaxoSmithKline, Switzerland; GlaxoSmithKline, Czech Republic; GlaxoSmithKline, Denmark; GlaxoSmithKline, United Kingdom; GlaxoSmithKline, Guyana; GlaxoSmithKline, Hungary; GlaxoSmithKline, Israel; GlaxoSmithKline, India; GlaxoSmithKline, Iran; GlaxoSmithKline, Kuwait; GlaxoSmithKline, Luxembourg; GlaxoSmithKline, Malta; GlaxoSmithKline, New Zealand; GlaxoSmithKline, Oman; GlaxoSmithKline, Qatar; Monarch, United States; Wellcome, Ireland; Wellcome Foundation, Slovakia



• Osnervan
  GlaxoSmithKline, Germany



• Perkinil
  Square, Bangladesh



• Procyclidine
  Remedica, Cyprus

International Drug Name Search

Glossary

BAN	British Approved Name
BANM	British Approved Name (Modified)
DCF	Dénomination Commune Française
DCIT	Denominazione Comune Italiana
OS	Official Synonym
PH	Pharmacopoeia Name
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Heparine Sodium

Heparine Sodium may be available in the countries listed below.

Ingredient matches for Heparine Sodium

Heparin

Heparin sodium salt (a derivative of Heparin) is reported as an ingredient of Heparine Sodium in the following countries:

• Turkey

International Drug Name Search

Ibu-Dent akut Heumann

Ibu-Dent akut Heumann may be available in the countries listed below.

Ingredient matches for Ibu-Dent akut Heumann

Ibuprofen

Ibuprofen is reported as an ingredient of Ibu-Dent akut Heumann in the following countries:

• Germany

International Drug Name Search

Asproaccel

Asproaccel may be available in the countries listed below.

Ingredient matches for Asproaccel

Aspirin

Acetylsalicylic Acid is reported as an ingredient of Asproaccel in the following countries:

• France

Caffeine

Caffeine is reported as an ingredient of Asproaccel in the following countries:

• France

International Drug Name Search

Salbutamol Sulphate

Salbutamol Sulphate may be available in the countries listed below.

Ingredient matches for Salbutamol Sulphate

Salbutamol

Salbutamol Sulphate (BANM) is also known as Salbutamol (Rec.INN)

International Drug Name Search

Glossary

BANM	British Approved Name (Modified)
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)

Click for further information on drug naming conventions and International Nonproprietary Names.

Halciderm

Halciderm may be available in the countries listed below.

Ingredient matches for Halciderm

Halcinonide

Halcinonide is reported as an ingredient of Halciderm in the following countries:

• Italy

Salicylic Acid

Salicylic Acid is reported as an ingredient of Halciderm in the following countries:

• Italy

International Drug Name Search

Lipofib

Lipofib may be available in the countries listed below.

Ingredient matches for Lipofib

Fenofibrate

Fenofibrate is reported as an ingredient of Lipofib in the following countries:

• Romania

International Drug Name Search

AK-Pred

In the US, AK-Pred (prednisolone ophthalmic) is a member of the drug class ophthalmic steroids and is used to treat Postoperative Ocular Inflammation.

US matches:

• AK-Pred Drops


• AK-Pred

Ingredient matches for AK-Pred

Prednisolone

Prednisolone is reported as an ingredient of AK-Pred in the following countries:

• Peru

Prednisolone 21-(disodium phosphate) (a derivative of Prednisolone) is reported as an ingredient of AK-Pred in the following countries:

• United States

International Drug Name Search

Herpex

Herpex may be available in the countries listed below.

Ingredient matches for Herpex

Acyclovir

Aciclovir is reported as an ingredient of Herpex in the following countries:

• Bahrain


• Ethiopia


• India


• Poland


• Portugal

Tromantadine

Tromantadine hydrochloride (a derivative of Tromantadine) is reported as an ingredient of Herpex in the following countries:

• Brazil

International Drug Name Search

Hidroclorotiazida MK

Hidroclorotiazida MK may be available in the countries listed below.

Ingredient matches for Hidroclorotiazida MK

Hydrochlorothiazide

Hydrochlorothiazide is reported as an ingredient of Hidroclorotiazida MK in the following countries:

• Colombia

International Drug Name Search

Biracin-E

Biracin-E may be available in the countries listed below.

Ingredient matches for Biracin-E

Tobramycin

Tobramycin is reported as an ingredient of Biracin-E in the following countries:

• Vietnam

International Drug Name Search

Sedotensil

Sedotensil may be available in the countries listed below.

Ingredient matches for Sedotensil

Lisinopril

Lisinopril is reported as an ingredient of Sedotensil in the following countries:

• Argentina

International Drug Name Search

betamethasone topical

Generic Name: betamethasone topical (bay ta METH a sone)

Brand names: Alphatrex, Beta-Val, Diprolene, Diprolene AF, Diprosone, Luxiq, ...show all 14 brand names.Uticort, Betanate, Del-Beta, Maxivate, Valisone, Betatrex, Betaderm, Teladar

What is betamethasone topical?

Betamethasone is a topical steroid. It reduces the actions of chemicals in the body that cause inflammation, redness, and swelling.

Betamethasone topical is used to treat the inflammation caused by a number of conditions such as allergic reactions, eczema, and psoriasis. The dental paste form of betamethasone is used to treat mouth ulcers.

Betamethasone topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about betamethasone topical?

Use this medication exactly as directed on the label, or as it has been prescribed by your doctor. Do not use the medication in larger amounts or for longer than recommended.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the skin that is treated with betamethasone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions.

Avoid using this medication on your face, near your eyes, or on body areas where you have skin folds or thin skin.

Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of betamethasone topical.

Betamethasone topical will not treat a bacterial, fungal, or viral skin infection.

Contact your doctor if your condition does not improve or if it gets worse after using this medication for several days.

What should I discuss with my healthcare provider before using betamethasone topical?

Do not use this medication if you are allergic to betamethasone.

Before using betamethasone topical, tell your doctor if you are allergic to any drugs, or if you have any type of skin infection.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether betamethasone topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of betamethasone topical.

How should I use betamethasone topical?

Use this medication exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor. Follow the instructions on your prescription label.

Betamethasone topical will not treat a bacterial, fungal, or viral skin infection.

Wash your hands before and after each application, unless you are using betamethasone topical to treat a hand condition.

Apply a small amount to the affected area and rub it gently into the skin.

Avoid using this medication on your face, near your eyes or mouth, or on body areas where you have skin folds or thin skin.

If you are using the dental paste, apply the medication in a thin layer, just enough to cover the mouth ulcer. The paste may stick better if you dry the mouth ulcer before applying the medication.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the skin that is treated with betamethasone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions. Contact your doctor if your condition does not improve or if it gets worse after using this medication for several days. It is important to use betamethasone topical regularly to get the most benefit. Store betamethasone topical at room temperature away from moisture and heat.

What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine, or if anyone has accidentally swallowed it. An overdose of betamethasone topical applied to the skin is not expected to produce life-threatening symptoms.

What should I avoid while using betamethasone topical?

Avoid getting this medication in your eyes, mouth, and nose, or on your lips. If it does get into any of these areas, wash with water. Do not use betamethasone topical on sunburned, windburned, irritated, or broken skin. Also avoid using this medication in open wounds.

Avoid using skin products that can cause irritation, such as harsh soaps or shampoos or skin cleansers, hair coloring or permanent chemicals, hair removers or waxes, or skin products with alcohol, spices, astringents, or lime. Do not use other medicated skin products unless your doctor has told you to.

Betamethasone topical side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these signs that you may be absorbing betamethasone topical through your skin or gums:

• 
  

  blurred vision, or seeing halos around lights;

  
  


• 
  

  uneven heartbeats;

  
  


• 
  

  mood changes;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  weight gain, puffiness in your face; or

  
  


• 
  

  feeling tired.

  
  

Less serious side effects may include:

• 
  

  skin redness, burning, itching, or peeling;

  
  


• 
  

  thinning of your skin; or

  
  


• 
  

  blistering skin; or

  
  


• 
  

  stretch marks.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Betamethasone topical Dosing Information

Usual Adult Dose for Dermatitis:

Topical: Apply a thin film to the affected area 1-3 times a day.
Foam: Apply twice daily (in morning and at night).

Usual Pediatric Dose for Dermatitis:

Cream, ointment and lotion:
>=13 years: Apply a thin film to the affected area 1-3 times a day.

What other drugs will affect betamethasone topical?

It is not likely that other drugs you take orally or inject will have an effect on topically applied betamethasone topical. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More betamethasone topical resources

• Betamethasone topical Use in Pregnancy & Breastfeeding
• Betamethasone topical Drug Interactions
• Betamethasone topical Support Group
• 13 Reviews for Betamethasone - Add your own review/rating

• Alphatrex Advanced Consumer (Micromedex) - Includes Dosage Information


• Beta-Val Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Beta-Val Advanced Consumer (Micromedex) - Includes Dosage Information


• Diprolene Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Diprolene Prescribing Information (FDA)


• Diprolene AF Prescribing Information (FDA)


• Luxiq Prescribing Information (FDA)


• Luxiq Foam MedFacts Consumer Leaflet (Wolters Kluwer)

Compare betamethasone topical with other medications

• Atopic Dermatitis
• Dermatitis
• Dermatological Disorders
• Lichen Planus
• Lichen Sclerosus

Where can I get more information?

• Your pharmacist can provide more information about betamethasone topical.

Estradiol Implant 25mg (Organon Laboratories Ltd)

1. Name Of The Medicinal Product

ESTRADIOL IMPLANT 25mg  

2. Qualitative And Quantitative Composition

Each implant contains 25mg estradiol.

3. Pharmaceutical Form

Implant

4. Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy for estrogen deficiency symptoms in postmenopausal women.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

4.2 Posology And Method Of Administration

Dosage and Administration

Dose

Adults: 25 - 100 mg

Estradiol implants are available in strengths of 25, 50 and 100mg. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used. In most patients, implantation of a 25mg dose provides relief of symptoms and prevents osteoporosis. Some patients may require 50 mg or even higher doses initially.

If possible, subsequent doses should be reduced stepwise (for example, 100mg to 50mg to 25mg), eventually using 25mg as a maintenance dose. Frequency of replacement depends on the duration of activity of the implants administered and the severity of the symptoms. Patients require a further implant when symptoms return, usually every 4 to 8 months.

Use of a progestagen

Women with an intact uterus:

Because of the sustained absorption of estradiol, the endometrium of post-menopausal or ovariectomised women is liable to progressive hypertrophy. Therefore, in women with an intact uterus, additional administration of a progestagen is recommended, for 12-14 days in each cycle, to prevent endometrial hyperplasia.

When the patient no longer requires or seeks re-implantation with estradiol pellets, it is recommended that, in those women with an intact uterus, cyclical administration of an oral progestagen should be continued until there is a cessation of withdrawal bleeding, in order to prevent the possibility of continued endometrial stimulation.

Hysterectomised women:

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

Administration

Estradiol implants should be inserted subcutaneously, (either by means of a trocar and cannula or in the wound at the time of laparotomy), into an area where there is relatively little movement or blood supply, such as the lower abdominal wall or the buttock. Insertion is made under local anaesthesia and the wound is closed either with an adhesive dressing or a fine suture.

Full aseptic 'no touch' technique should be adopted.

Removal of the implant

Since the implant consists entirely of estradiol without any auxilliary ingredients, it is biodegradable and no removal procedure is required. In the rare event that removal of the implant should be necessary, the implant may be located by palpation or, if not successful, by Magnetic Resonance Imaging. This technique can identify the implant by its size and structure. The implant can then be precisely located by insertion of a localiser wire with the tip ending at the implant. After locating the implant, it can be removed following a small incision under local anaesthetic.

Starting/switching treatment

An Estradiol implant may be inserted immediately in women experiencing a surgical menopause.

In women not taking HRT or who are changing from a continuous-combined HRT product, an Estradiol implant may be inserted at any time. In women who are switching from a sequential HRT regimen, the implant should be inserted right after the withdrawal bleeding has ended.

4.3 Contraindications

• Known, past or suspected breast cancer.

• Known or suspected estrogen-dependent malignant tumours (e.g endometrial cancer).

• Undiagnosed genital bleeding.

• Untreated endometrial hyperplasia.

• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism).

• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).

• Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal

• Known hypersensitivity to the active substance.

• Porphyria.

4.4 Special Warnings And Precautions For Use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications (section 4.3) and warnings for use (section 4.4). During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see “Breast cancer” below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Estradiol implants, in particular:

• Leiomyoma (uterine fibroids) or endometriosis.

• A history of, or risk factors for, thromboembolic disorders (see below).

• Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer.

• Hypertension.

• Liver disorders (e.g. liver adenoma).

• Diabetes mellitus with or without vascular involvement.

• Cholelithiasis.

• Migraine or (severe) headache.

• Systemic lupus erythematosus.

• A history of endometrial hyperplasia (see below)

• Epilepsy.

• Asthma.

• Otosclerosis.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

• Jaundice or deterioration in liver function.

• Significant increase in blood pressure.

• New onset of migraine-type headache.

• Pregnancy.

Endometrial hyperplasia

• The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk.

• The endometrial safety of Estradiol implants with the addition of progestagen in women with an intact uterus has not been studied in clinical trials.

• Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

• Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis (but see above).

Breast cancer

A randomised placebo-controlled trial, the Women's Health Initiative Study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of use but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI Study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Long-term (at least 5 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.

Venous thromboembolism

• HRT is associated with a higher risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a 2-3 fold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT use than later.

• Generally recognised risk factors for VTE include a personal or family history, severe obesity (Body Mass Index >30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

• Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

• If VTE develops after initiating therapy the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Other conditions

• Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of the circulating active ingredient in Estradiol implants is increased.

• Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

• Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

• There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's wort (Hypericum Perforatum) may induce the metabolism of estrogens.

Since Estradiol implants are administered parentally, the first-pass effect in the liver is avoided and, thus, parentally administered estrogens might be less affected than oral hormones by enzyme inducers.

Clinically, an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

4.6 Pregnancy And Lactation

Estradiol implants are not indicated during pregnancy. If pregnancy occurs during medication with Estradiol implants treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.

Estradiol implants are not indicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

As far as known Estradiol implants have no effect on alertness or concentration.

4.8 Undesirable Effects

The following adverse reactions have been associated with estrogen therapy in general.

Genito-urinary tract:

Intermenstrual bleeding, increase in the size of the uterine fibromyomata, endometrial proliferation, excessive production of cervical mucus, aggravation of endometriosis, pre-menstrual like syndrome.

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

Breast:

Tenderness, pain, enlargement, secretion.

Breast cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

Ø For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

Ø For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

Ø For users of estrogen-only replacement therapy

• between 0 and 3 (best estimate = 1.5) for 5 years' use

• between 3 and 7 (best estimate = 5) for 10 years' use.

Ø For users of estrogen plus progestagen combined HRT,

• between 5 and 7 (best estimate = 6) for 5 years' use

• between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

Ø For 1000 women in the placebo group,

• about 16 cases of invasive breast cancer would be diagnosed in 5 years.

Ø For 1000 women who used estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be

• between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Gastro-intestinal tract:

Nausea, vomiting, cholelithiasis, cholestatic jaundice, gall bladder disease. Changes in liver function.

Cardiovascular system:

Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

Myocardial infarction and stroke, thrombosis, rise of blood pressure.

Skin and subcutaneous disorders:

Chloasma, erythema nodosum, erythema multiforme, vascular purpura, rash.

Eyes:

Discomfort of the cornea if contact lenses are used.

CNS:

Headache, migraine, mood changes. Probable dementia (see section 4.4).

Metabolic:

Sodium and water retention, reduced glucose tolerance, and change in body weight.

High dosages and/or prolonged use of estrogens may cause psychotic disturbances.

Prolonged exposure to estrogens may increase risk of development of cardiac and renal disease, estrogen-dependant neoplasms benign and malignant, e.g. melanoma, otosclerosis, multiple sclerosis and systemic lupus erythematosus.

4.9 Overdose

Acute overdose with Estradiol implants is not known to occur.

With chronic use supraphysiological levels of estradiol can be found, however these do not generally result in adverse symptoms, signs or metabolic effects. None the less it would seem prudent in the circumstances to withhold further implantation or other administration of exogenous estrogens until estradiol levels have fallen to within the pre-menopausal physiological range.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Estradiol/Estradiol valerate: The active ingredient, synthetic 17-estradiol is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

Clinical Trial Information

• Relief of estrogen-deficiency symtoms and bleeding patterns

Relief of menopausal symptoms was achieved usually during the first week of treatment.

• Prevention of osteoporosis

- Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

- Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

- Studies have reported significant increases in bone mineral density at spine and hip after treatment with Estradiol implants (25-100 mg every 6 months) for 1 to 15.5 years.

5.2 Pharmacokinetic Properties

After insertion of an Estradiol implant 25mg, into the subcutaneous fat the estradiol plasma level reaches its maximum of about 400 pmol/l in a few weeks and shows a slow and gradual decline to about 150 pmol/l at 6 months. As with other estrogens, there are large interindividual differences in estradiol levels, but intraindividual variability appears to be small. Unlike oral estrogen therapy, subcutaneous administration bypasses the gastrointestinal tract, where estradiol is converted to estrone and avoids the first-pass effect of the liver. Therefore more unconjugated estradiol is observed and the liver is less burdened.

The transport, metabolism, and excretion of estradiol released from the implants are comparable to those of endogenous estradiol. Thus, about 38 per cent of circulatory estradiol will be bound to SHBG, 60 per cent is bound to albumin, and only 2-3 per cent is free. The main metabolic end products are estriol and 2-hydroxyestrone, which are synthesised after conversion of estradiol to estrone. Most of the estradiol is excreted by the kidneys, mainly after conjugation with glucuronic and sulphuric acid. There is a significant enterohepatic circulation of estradiol and its metabolites. Most of the conjugated biliary estrogens undergo hydrolysis in the intestines after which they are reabsorbed. Therefore, only a small part of the administered estradiol will ultimately be lost in the faeces.

After long-term treatment, accumulation may occur (with doses of 50 mg or more, especially when reimplantation is performed after periods of less than 6 months), but in most cases there is only a moderate increase and levels remain well within the normal premenopausal range. However, in rare cases (mainly with implantation intervals of only 3 or 4 months) plasma levels may rise above 1750 pmol/l. There are some indications that supraphysiological levels occur most frequently in women with a history of depression or surgical castration.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Estradiol implants contain no auxiliary ingredients.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

Each sterile implant is supplied singly, in a sealed glass tube.

6.6 Special Precautions For Disposal And Other Handling

Full aseptic 'no-touch' technique should be used.

Administrative Data

7. Marketing Authorisation Holder

Organon Laboratories Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0FL, U.K.

8. Marketing Authorisation Number(S)

0065/5074R

9. Date Of First Authorisation/Renewal Of The Authorisation

31/8/87 Renewed 06/07/1995

10. Date Of Revision Of The Text

May 2005

Ref: US06ESTRADIOL25v1.1