Acyclovir

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

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 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

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

Decreased acyc

Cefzil

Generic Name: cefprozil (sef PROE zil)

Brand Names: Cefzil

What is cefprozil?

Cefprozil is in a group of drugs called cephalosporin (SEF a low spor in) antibiotics. It works by fighting bacteria in your body.

Cefprozil is used to treat many different types of infections caused by bacteria.

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

What is the most important information I should know about cefprozil?

Do not take this medication if you are allergic to cefprozil, or to similar antibiotics, such as Ceftin, Keflex, Omnicef, and others.

Before taking this medication, tell your doctor or if you are allergic to any drugs (especially penicillins). Also tell your doctor if you have kidney disease or a history of intestinal problems.

Take this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Cefprozil will not treat a viral infection such as the common cold or flu.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or has blood in it, call your doctor. Do not use any medicine to stop the diarrhea unless your doctor has told you to.

The cefprozil suspension (liquid) may contain phenylalanine. Talk to your doctor before using this form of cefprozil if you have phenylketonuria (PKU).

What should I discuss with my healthcare provider before taking cefprozil?

Do not take this medication if you are allergic to cefprozil or to other cephalosporin antibiotics, such as:

• 
  

  cefaclor (Raniclor);

  
  


• 
  

  cefadroxil (Duricef);

  
  


• 
  

  cefazolin (Ancef);

  
  


• 
  

  cefdinir (Omnicef);

  
  


• 
  

  cefditoren (Spectracef);

  
  


• 
  

  cefpodoxime (Vantin);

  
  


• 
  

  ceftibuten (Cedax);

  
  


• 
  

  cefuroxime (Ceftin);

  
  


• 
  

  cephalexin (Keflex); or

  
  


• 
  

  cephradine (Velosef).

  
  

Before taking cefprozil, tell your doctor if you are allergic to any drugs (especially penicillins) or if you have:

• 
  

  kidney disease (or if you are on dialysis); or

  
  


• 
  

  a history of intestinal problems, such as colitis.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take cefprozil.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Cefprozil may pass into breast milk and could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

The cefprozil suspension (liquid) may contain phenylalanine. Talk to your doctor before using this form of cefprozil if you have phenylketonuria (PKU).

How should I take cefprozil?

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

Take this medicine with a full glass of water. Shake the oral suspension (liquid) well just before you measure a dose. To be sure you get the correct dose, measure the liquid with a marked measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

This medication can cause you to have false results with certain medical tests, including urine glucose (sugar) tests. Tell any doctor who treats you that you are using cefprozil.

Take cefprozil for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated. Cefprozil will not treat a viral infection such as the common cold or flu. Store cefprozil tablets at room temperature away from moisture, heat, and light. Store cefprozil oral liquid in the refrigerator. Do not allow it to freeze. Throw away any unused medication that is older than 14 days.

What happens if I miss a dose?

Take the medication as soon as you remember the missed dose. If it is almost time for your next dose, skip the missed dose and use the medicine at your 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.

Overdose symptoms may include loss of appetite and diarrhea.

What should I avoid while taking cefprozil?

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or has blood in it, call your doctor. Do not use any medicine to stop the diarrhea unless your doctor has told you to.

Cefprozil 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. Call your doctor at once if you have any of these serious side effects:

• 
  

  diarrhea that is watery or bloody;

  
  


• 
  

  fever, chills, body aches, flu symptoms;

  
  


• 
  

  unusual bleeding;

  
  


• 
  

  seizure (convulsions);

  
  


• 
  

  pale or yellowed skin, dark colored urine, fever, confusion or weakness;

  
  


• 
  

  jaundice (yellowing of the skin or eyes);

  
  


• 
  

  fever, sore throat, and headache with a severe blistering, peeling, and red skin rash;

  
  


• 
  

  skin rash, bruising, severe tingling, numbness, pain, muscle weakness; or

  
  


• 
  

  increased thirst, loss of appetite, swelling, weight gain, feeling short of breath, urinating less than usual or not at all.

  
  

Less serious side effects may include:

• 
  

  nausea, vomiting, stomach pain, mild diarrhea;

  
  


• 
  

  stiff or tight muscles;

  
  


• 
  

  dizziness, feeling restless or hyperactive;

  
  


• 
  

  unusual or unpleasant taste in your mouth;

  
  


• 
  

  diaper rash in an infant taking liquid cefprozil;

  
  


• 
  

  mild itching or skin rash; or

  
  


• 
  

  vaginal itching or discharge.

  
  

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.

What other drugs will affect cefprozil?

Before taking cefprozil, tell your doctor if you are using any of the following drugs:

• 
  

  probenecid (Benemid);

  
  


• 
  

  an antibiotic such as amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Mycifradin, Neo-Fradin, Neo-Tab), netilmicin (Netromycin), paromomycin (Humatin, Paromycin), streptomycin, tobramycin (Nebcin, Tobi); or

  
  


• 
  

  a diuretic (water pill) such as bumetanide (Bumex), furosemide (Lasix), indapamide (Lozol), hydrochlorothiazide (HCTZ, HydroDiuril, Hyzaar, Lopressor, Vasoretic, Zestoretic), metolazone (Mykrox, Zarxolyn), spironolactone (Aldactazide, Aldactone), torsemide (Demadex), and others.

  
  

This list is not complete and there may be other drugs that can interact with cefproziloxime. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start taking a new medication without telling your doctor.

More Cefzil resources

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

• Cefzil Prescribing Information (FDA)


• Cefzil Consumer Overview


• Cefzil Monograph (AHFS DI)


• Cefzil Advanced Consumer (Micromedex) - Includes Dosage Information


• Cefzil MedFacts Consumer Leaflet (Wolters Kluwer)


• Cefprozil Professional Patient Advice (Wolters Kluwer)


• Cefprozil Prescribing Information (FDA)

Compare Cefzil with other medications

• Bladder Infection
• Bronchitis
• Kidney Infections
• Otitis Media
• Pneumonia
• Sinusitis
• Skin Infection
• Tonsillitis/Pharyngitis
• Upper Respiratory Tract Infection

Where can I get more information?

• Your pharmacist can provide more information about cefprozil.

See also: Cefzil side effects (in more detail)

Niaspan Prolonged-Release Tablets Starter Pack

1. Name Of The Medicinal Product

Niaspan Prolonged-Release Tablets- Starter Pack

2. Qualitative And Quantitative Composition

Starter Pack contains 7 tablets each:

Prolonged-Release Tablets containing 375 mg nicotinic acid

Prolonged-Release Tablets containing 500 mg nicotinic acid

Prolonged-Release Tablets containing 750 mg nicotinic acid

For excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablets

White to off-white capsule-shaped tablets. Each tablet is embossed with the tablet strength on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of dyslipidaemia, particularly in patients with combined mixed dyslipidaemia, characterised by elevated levels of LDL-cholesterol and triglycerides and low HDL-cholesterol, and in patients with primary hypercholesterolaemia. Niaspan should be used in patients in combination with HMG-CoA reductase inhibitors (statins), when the cholesterol lowering effect of HMG-CoA reductase inhibitor monotherapy is inadequate. Niaspan can be used as monotherapy only in patients who do not tolerate HMG-CoA reductase inhibitors. Diet and other non-pharmacological treatments (e.g. exercise, weight reduction) should be continued during therapy with Niaspan.

4.2 Posology And Method Of Administration

Niaspan Prolonged-Release Tablets Starter Pack is only a starter pack presentation for initial dose titration.

Niaspan should be taken at bedtime, after a low-fat snack (e.g. an apple, low fat yoghurt, slice of bread) and doses should be individualised according to the patient's response.

Initial dose

Therapy with Niaspan must be initiated with a low dose and increased gradually. The recommended dose escalation schedule is shown below in Table 1:

Table 1: Dose escalation schedule

	Week(s)	Dosage		Daily nicotinic acid dose
↑	1	Niaspan 375mg	1 tablet at bedtime	375mg	↑
INITIAL TITRATION SCHEDULE	2	Niaspan 500mg	1 tablet at bedtime	500mg	TITRATION STARTER PACK
	3	Niaspan 750mg	1 tablet at bedtime	750mg
	4-7	Niaspan 500mg	2 tablets at bedtime	1000mg
		Niaspan 750mg	2 tablets at bedtime	1500mg
		Niaspan 1000mg	2 tablets at bedtime	2000mg

Maintenance dose

The recommended maintenance dose is 1000mg (two 500mg tablets) to 2000mg (two 1000mg tablets) once daily at bedtime depending on the patient's response and tolerance. If the response to 1000mg daily is inadequate, the dose may be increased to 1500mg daily and subsequently to 2000mg daily.

The daily dosage of Niaspan should not be increased by more than 500mg in any four-week period after the initial titration to 1000mg. The maximum dose is 2000mg per day.

The different Niaspan tablet strengths have different bioavailability and are therefore not interchangeable.

Niaspan must not be replaced with other nicotinic acid preparations, see section 4.4.

In patients previously treated with other nicotinic acid products, Niaspan treatment must be initiated with the recommended Niaspan dose escalation schedule. The maintenance dose should subsequently be individualised according to the patient's response.

If Niaspan therapy is discontinued for an extended period, re-institution of therapy must include a dose escalation.

Niaspan tablets must not be broken, crushed or chewed before swallowing.

Renal impairment

No studies have been performed in patients with impaired renal function, Niaspan must be used with caution in patients with renal disease.

Hepatic impairment

No studies have been performed in patients with impaired hepatic function. Niaspan must be used with caution in patients with a history of liver disease and who consume substantial quantities of alcohol, see section 4.4. Niaspan is contraindicated in patients with significant hepatic dysfunction, see section 4.3.

Elderly

No dose adjustment is necessary.

Children

The safety and efficacy of nicotinic acid therapy in children and adolescents has not been established. Use in children and adolescents is not recommended.

4.3 Contraindications

Niaspan is contraindicated in patients with

- hypersensitivity to nicotinic acid or to any of the excipients, see section 6.1,

- significant hepatic dysfunction,

- active peptic ulcer disease,

- arterial bleeding.

4.4 Special Warnings And Precautions For Use

Niaspan must not be replaced with other nicotinic acid preparations. When switching from other nicotinic acid preparations to Niaspan, therapy with Niaspan must be initiated with the recommended dose escalation schedule, see section 4.2.

Liver

Nicotinic acid preparations have been associated with abnormal liver tests. Severe hepatic toxicity, including fulminant hepatic necrosis, has occurred in patients who have taken long-acting nicotinic acid products in place of immediate-release nicotinic acid. Since the pharmacokinetics of Niaspan are different to other nicotinic acid preparations, Niaspan must not be replaced with other preparations. The prescribing information of the HMG-CoA reductase inhibitor should also be consulted for warnings and precautions for use.

Caution is advised when Niaspan is used in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

Elevated liver transaminases have been observed with Niaspan therapy. However, transaminase elevations were reversible upon discontinuation of Niaspan.

Liver tests including AST and ALT must be performed periodically in all patients during therapy with Niaspan and prior to treatment in case of history and/or symptoms of hepatic dysfunction (e.g. jaundice, nausea, fever, and/or malaise). If the transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal, the drug must be discontinued.

Skeletal muscle

Reports of rhabdomyolysis in patients on combined therapy with Niaspan and HMG-CoA reductase inhibitors have been received from spontaneous reporting. Physicians contemplating combined therapy with HMG-CoA reductase inhibitors and Niaspan should carefully weigh the potential benefits and risks and should carefully monitor patients for any symptoms of rhabdomyolysis e.g. muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations.

A CPK level should be measured before starting such a combination in patients with pre-disposing factors for rhabdomyolysis, as follows:

• renal impairment

• hypothyroidism

• alcohol abuse

• age > 70 years

• personal or family history of hereditary muscular disorders

• previous history of muscular toxicity with fibrate or HMG-CoA reductase inhibitor

Muscle damage must be considered in any patient presenting with diffuse myalgia, muscle tenderness and/or marked increase in muscle CK levels (>5 x ULN); under these conditions treatment must be discontinued.

The prescribing information of the HMG-CoA reductase inhibitors should be consulted.

Glucose Intolerance

Diabetic or potentially diabetic patients should be observed closely since there may be a dose-related increase in glucose intolerance. Adjustment of diet and/or oral antidiabetics and/or insulin therapy may become necessary.

Unstable angina and acute myocardial infarction

Caution is advised when Niaspan is used in patients with unstable angina or in the acute phase of myocardial infarction, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents.

Uric acid

Elevated uric acid levels have occurred with Niaspan therapy. Monitoring of patients predisposed to gout is recommended.

Coagulation

Niaspan may affect platelet count and prothrombin time, see section 4.5. Patients undergoing surgery should be carefully evaluated. Caution is also advised when Niaspan is administered concomitantly with anti-coagulants; patients receiving anti-coagulants must be monitored closely for prothrombin time and platelet count.

Hypophosphataemia

Niaspan has been associated with reductions in phosphorous levels. Although these reductions were transient, monitoring of phosphorous levels is recommended in patients at risk of hypophosphataemia.

Other

Patients with a history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Niaspan therapy.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant alcohol or hot drinks may increase undesirable flushing and pruritus and should be avoided around the time of Niaspan ingestion.

Niaspan has been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000mg). In addition, Niaspan has been associated with small but statistically significant increases in prothrombin time (mean of approximately +4%). When Niaspan is administered concomitantly with anti-coagulants, prothrombin time and platelet counts must be monitored closely.

Nicotinic acid may potentiate the blood-pressure lowering effect of ganglionic blocking agents e.g. transdermal nicotine or vasoactive drugs such as nitrates, calcium channel blockers or adrenergic blocking agents.

Bile acid sequestrants bind to other orally administered medicinal products and should be taken separately, see also prescribing information of the concerned product.

Nicotinic acid may produce false elevations in some fluorometric determinations of plasma or urinary catecholamines. Nicotinic acid may also give false-positive reactions with cupric sulphate solution (Benedict's reagent) in urine glucose tests.

Combination of nicotinic acid with HMG-CoA reductase inhibitors may increase the risk for myopathy and rhabdomyolysis, see also section 4.4. The prescribing information of the HMG-CoA reductase inhibitor should also be consulted.

4.6 Pregnancy And Lactation

Pregnancy

It is not known whether nicotinic acid at doses typically used for lipid disorders can cause foetal harm when administered to pregnant women or whether it can affect reproductive capacity. Animal studies are incomplete, see section 5.3.

Niaspan should not be prescribed to pregnant women unless strictly necessary.

Lactation

Nicotinic acid has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants from lipid-altering doses of nicotinic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No studies have been conducted with Niaspan in nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

Niaspan has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Flush

In the placebo-controlled clinical trials, flushing episodes (i.e. warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse events for Niaspan (reported by 88% of patients). In these studies fewer than 6% of Niaspan patients discontinued due to flushing.

In comparisons of immediate-release (IR) nicotinic acid and Niaspan, although the number of patients who flushed was similar, fewer flushing episodes were reported by patients who received Niaspan. Following four weeks of maintenance therapy with Niaspan at daily doses of 1500mg, the frequency of flushing over the four week period averaged 1.88 events per patient.

Flushing reactions generally occur during early treatment and the dose titration phase. They are thought to be mediated by the release of prostaglandin D2 and tolerance to flushing usually develops over the course of several weeks.

Spontaneous reports suggest that in rare cases, flushing may be more severe and accompanied by symptoms of dizziness, tachycardia, palpitations, dyspnoea, sweating, chills and/or oedema which in rare cases may lead to syncope. Medical treatment should be administered as necessary.

Hypersensitivity reactions

Hypersensitivity reactions have been reported very rarely. These may be characterised by symptoms such as generalised exanthema, flush, urticaria, vesiculobullous rash, angioedema, laryngospasm, dyspnoea, hypotension, and circulatory collapse. Medical treatment should be administered as necessary.

The following adverse reactions have been observed in clinical studies or in routine patient management, in patients receiving the recommended daily maintenance doses (1000, 1500, and 2000mg) of Niaspan. They are presented by system organ class and frequency grouping (very common >1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000, including isolated reports). In general, the incidence of adverse reactions was higher in women compared to men. (Please refer to Table 2 below).

Table 2: Adverse reactions

Organ Class	Very common >1/10	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000	Very rare <1/10,000, including isolated reports
Immune system disorders					Hypersensitivity
Metabolism and nutrition disorders				Glucose tolerance decreased	Anorexia, gout
Psychiatric disorders				Insomnia, nervousness
Nervous system disorders			Headache, dizziness	Syncope, paraesthesia	Migraine
Eye disorders				Visual impairment	Amblyopia, cystoid macular oedema
Cardiac disorders			Tachycardia, palpitations		Atrial fibrillation, arrhythmia
Vascular disorders	Flushing			Hypotension, orthostatic hypotension	Collapse
Respiratory, thoracic and mediastinal disorders			Dyspnoea	Rhinitis
Gastrointestinal disorders		Diarrhoea, nausea, vomiting, abdominal pain, dyspepsia		Flatulence, eructation	Peptic ulcers
Hepatobiliary disorders					Jaundice
Skin and subcutaneous tissue disorders		Pruritus, rash	Hyperhidrosis, rash generalised, urticaria, dry skin	Face oedema, dermatitis bullous, rash maculopapular	Skin hyperpigmentation, acanthosis nigricans
Musculoskeletal, connective tissue and bone disorders				Muscle spasms, myalgia, myopathy, myasthenia
General disorders and administration site conditions			Pain, asthenia, chills, oedema peripheral	Chest pain
Investigations			Aspartate aminotransferase increased; alanine aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased, blood lactate dehydrogenase increased, blood amylase increased, blood glucose increased, blood uric acid increased, platelet count decreased, prothrombin time prolonged, blood phosphorus decreased, blood creatinine phospokinase increased

Adverse reactions from postmarketing experience:

The following adverse reactions have been reported in postmarketing experience with nicotinic acid prolonged release. Adverse reactions are presented by system organ class.

Nervous system disorders: Burning sensation

Eye disorders: Blurred vision

Hepatobiliary disorders: Hepatitis

Skin and subcutaneous tissue disorders: Skin discolouration, skin burning sensation, erythema

General disorders and administration site conditions: Feeling hot

4.9 Overdose

Information on acute overdose with Niaspan in humans is limited. The signs and symptoms of an acute overdose are anticipated to be those of excessive pharmacological effect: severe flushing, nausea/vomiting, diarrhoea, dyspepsia, dizziness, syncope, hypotension, potential cardiac arrhythmias and clinical laboratory abnormalities including elevations in liver function tests. The patient should be carefully observed and given supportive treatment. Insufficient information is available on the dialysis potential of nicotinic acid.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: nicotinic acid, ATC code: C10AD02

Nicotinic acid is a water-soluble B-complex vitamin which is a naturally occurring constituent of foods. The human body is not entirely dependent on dietary sources of nicotinic acid, since it may also be synthesised from tryptophan.

The mechanism of action by which nicotinic acid modify lipid profiles is not fully elucidated. However, it is recognised that nicotinic acid inhibits the release of free fatty acids from adipose tissue resulting in less free fatty acids being presented to the liver. Since fewer fatty acids are being transported to the liver, fewer are esterified to triglycerides and then incorporated into VLDL. This may lead to a decrease in LDL generation. By increasing lipoprotein lipase activity, nicotinic acid may increase the rate of chylomicron triglycerides removal from plasma. Thus, nicotinic acid decreases the rate of hepatic synthesis of VLDL and subsequently LDL. It does not appear to affect faecal excretion of fats, sterols, or bile acids.

At the recommended maintenance dose, Niaspan (but not nicotinamide) resulted in a clinical reduction in total cholesterol to HDL ratio [-17, to -27%], LDL [-8 to -16%], triglycerides [-14 to -35%] with an increase in HDL [16% to 26%]. In addition to the above mentioned reduction in LDL levels, nicotinic acid causes a shift in LDL composition from the small dense LDL particles (major atherogenic lipoprotein) to the larger, more buoyant LDL particles (less atherogenic). The increase in HDL is also associated with a shift in the distribution of HDL sub-fractions including an increase in the HDL2 to HDL3 ratio, the protective effect of HDL being mainly due to HDL2. Moreover, nicotinic acid increases serum levels of apolipoprotein A1 (Apo 1), one of the two major lipoproteins of HDL, while decreases concentrations of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions known to play important roles in atherogenesis. The serum levels of lipoprotein a, [Lp (a)], which present great homology with LDL but considered as an independent risk factor for coronary heart disease, are also significantly reduced by Niaspan.

Data from clinical trials suggest that women have a greater hypolipidaemic response than men at equivalent doses of Niaspan.

There are no specific studies of the combination of Niaspan with statins.

The beneficial effect of Niaspan on morbidity and mortality has not been directly assessed. However, relevant clinical data are available with immediate release (IR) nicotinic acid.

5.2 Pharmacokinetic Properties

Absorption

Nicotinic acid is rapidly and extensively absorbed when administered orally (at least 60-76% of dose).

Peak steady-state nicotinic acid concentrations were 0.6, 4.9, and 15.5 microgram/ml after doses of 1000, 1500, and 2000mg Niaspan once daily (given as two 500mg, two 750mg, and two 1000mg tablets, respectively).

Single-dose bioavailability studies have demonstrated that Niaspan tablet strengths are not interchangeable.

Distribution

Studies using radio-labelled nicotinic acid in mice show that nicotinic acid and its metabolites concentrate in the liver, kidney and adipose tissue.

Metabolism

The pharmacokinetic profile of nicotinic acid is complicated due to rapid and extensive first-pass metabolism which is species and dose-rate specific. In humans, one pathway (Pathway 1) is through a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted in the urine, although there may be a small amount of reversible metabolism back to nicotinic acid. There is evidence to suggest that nicotinic acid metabolism along this pathway leads to flush. The other pathway (Pathway 2) results in the formation of nicotinamide adenine dinucleotide (NAD). A predominance of metabolism down Pathway 2 may lead to hepatotoxicity. It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolised to at least N-methylnicotinamide (MNA) and nicotinamide N-oxide (NNO). MNA is further metabolised to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans. At the doses used to treat hyperlipidaemia, these metabolic pathways are saturable, which explains the non-linear relationship between nicotinic acid dose and plasma concentrations following multiple dose Niaspan administration.

Nicotinamide does not have hypolipidaemic activity; the activity of the other metabolites is unknown.

Elimination

Nicotinic acid and its metabolites are rapidly eliminated in the urine. Following single and multiple doses, approximately 60-76% of the dose administered as Niaspan was recovered in the urine as nicotinic acid and metabolites; up to 12% was recovered as unchanged nicotinic acid after multiple dosing. The ratio of metabolites recovered in the urine was dependent on the dose administered.

Gender differences

Steady state plasma concentrations of nicotinic acid and metabolites after administration of Niaspan are generally higher in women than in men, with the magnitude of difference varying with dose and metabolite. Recovery of nicotinic acid and metabolites in urine, however, is generally similar for men and women, indicating the absorption is similar for both genders. The gender differences observed in plasma levels of nicotinic acid and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution.

5.3 Preclinical Safety Data

Nicotinic acid has been shown to be of low toxicity in customary animal studies.

Female rabbits have been dosed with 0.3g nicotinic acid per day from pre-conception to lactation, and gave birth to offspring without teratogenic effects. Further specific animal reproduction studies have not been conducted with nicotinic acid or with Niaspan.

In a life-time study in mice, high dose levels of nicotinic acid showed no treatment-related carcinogenic effects and no effects on survival rates.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Povidone

Hypromellose

Stearic acid

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C

Blister: Store in the original package to protect from moisture

6.5 Nature And Contents Of Container

Starter Pack: Niaspan Prolonged Release Tablets Starter Pack are presented in a 21 tablet starter pack containing three weeks supply of medication packed in three individually sealed strips (PVC/Chlortrifluoroethylene/PE/aluminium) as follows:

Week 1: seven Niaspan 375mg Prolonged Release Tablets

Week 2: seven Niaspan 500mg Prolonged Release Tablets

Week 3: seven Niaspan 750mg Prolonged Release Tablets

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Abbott Laboratories Ltd.,

Abbott House,

Vanwall Business Park,

Vanwall Road,

Maidenhead,

Berkshire,

SL6 4XE,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 00037/0635

9. Date Of First Authorisation/Renewal Of The Authorisation

04^th June 2009

10. Date Of Revision Of The Text

28^th January 2011