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STAVUDINE

REMEDYREPACK INC.


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

BOXED WARNING




LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING STAVUDINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF STAVUDINE AND DIDANOSINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF STAVUDINE AND DIDANOSINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY ).

FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WHEN STAVUDINE WAS PART OF A COMBINATION REGIMEN THAT INCLUDED DIDANOSINE IN BOTH TREATMENT-­NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION (SEE WARNINGS).

STAVUDINE DESCRIPTION







STAVUDINE




MICROBIOLOGY




i

Antiviral Activity

50

Drug Resistance

50

Cross-resistance


CLINICAL PHARMACOLOGY




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Table 1: Steady-State Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults
Parameter Stavudine 40 mg BID
Mean ± SD
(n=8)
a from 0 to 24 hours.
AUC = area under the curve over 24 hours.
Cmax = maximum plasma concentration.
Cmin = trough or minimum plasma concentration.
AUC (ng•h/mL)a
2568 ± 454
Cmax (ng/mL)
 536 ± 146
Cmin (ng/mL)
 8 ± 9







14N-



14


Table 2: Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults: Bioavailability, Distribution, and Clearance
Parameter  Mean ± SD       n   
a following 1-hour IV infusion.
b following single oral dose.
c assuming a body weight of 70 kg.
d over 12 to 24 hours.
Oral bioavailability (%)
 
 Volume of distribution (L)a
 
 Total body clearance (mL/min)a
 
 Apparent oral clearance (mL/min)b
 
 Renal clearance (mL/min)a
 
 Elimination half-life, IV dose (h)a
 
 Elimination half-life, oral dose (h)b
 
 Urinary recovery of stavudine (% of dose)a,d 
86.4 ± 18.2
 
46 ± 21
 
594 ± 164
 
560 ± 182c
 
237 ± 98
 
1.15 ± 0.35
 
1.6 ± 0.23
 
42 ± 14
25   
 
   44   
 
   44   
 
    113     
 
   39   
 
   44   
 
   8   
 
   39   






Table 3: Pharmacokinetic Parameters (Mean ± SD) of Stavudine in HIV-Exposed or –Infected Pediatric Patients
Parameter Ages 5
 weeks to
15 years 		   n    Ages 14 to
 28 days 		   n    Day of
 Birth 		   n   
a following 1-hour IV infusion.
b   at median time of 2.5 hours (range 2 to 3 hours) following multiple oral doses.
c  following single oral dose.
d  over 8 hours.
ND = not determined.
Oral bioavailability (%)
76.9 ± 31.7
 20   
 ND
ND
Volume of distribution (L/kg)a
0.73 ± 0.32
 21   
 ND
ND
Ratio of CSF: plasma concentrations (as %)b 
59 ± 35
 8   
 ND
ND
Total body clearance (mL/min/kg)a
9.75 ± 3.76
 21   
 ND
ND
Apparent oral clearance (mL/min/kg)c
13.75 ± 4.29 
20   
 11.52 ± 5.93 
30     
 5.08 ± 2.8
 17     
Elimination half-life, IV dose (h)a
1.11 ± 0.28
 21   
 ND
ND
Elimination half-life, oral dose (h)c
0.96 ± 0.26
 20     
 1.59 ± 0.29
 30   
 5.27 ± 2.01 
17   
Urinary recovery of stavudine (% of dose)c,d 
34 ± 16
 19   
 ND
ND


maxmax DOSAGE AND ADMINISTRATION
Table 4: Mean ± SD Pharmacokinetic Parameter Values of Stavudinea in Adults with Varying Degrees of Renal Function

Creatinine Clearance Hemodialysis
Patientsb
 (n=11)
Less then 50 mL/min 
(n=10) 		26 to 50 mL/min 
(n=5) 		9 to 25 mL/min 
(n=5)
a Single 40 mg oral dose.
b Determined while patients were off dialysis.
T½ = terminal elimination half-life.
NA = not applicable.
Creatinine clearance (mL/min)
 
 Apparent oral clearance (mL/min)
 
 Renal clearance (mL/min)
 
 T½ (h)
104 ± 28
 
335 ± 57
 
167 ± 65
 
1.7 ± 0.4
 41 ± 5
 
191 ± 39
 
73 ± 18
 
3.5 ± 2.5
 17 ± 3
 
116 ± 25
 
17 ± 3
 
4.6 ± 0.9
 NA
 
105 ± 17
 
NA
 
5.4 ± 1.4






PRECAUTIONS: Geriatric Use .












DRUG INTERACTIONS



(see PRECAUTIONS: Drug Interactions )

Zidovudine:

Doxorubicin: In vitro 

Ribavirin: In vitro WARNINGS





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Table 5: Results of Drug Interaction Studies with Stavudine: Effects of Coadministered Drug on Stavudine Plasma AUC and Cmax Values
Drug Stavudine
  Dosage 		na    AUC of
Stavudine
 (95% CI) 		Cmax of
 Stavudine
(95% CI)
↑ indicates increase
↔ indicates no change, or mean increase or decrease of greater then 10%.
a HIV-infected patients.
Didanosine, 100 mg
q12h for 4 days
 40 mg q12h
for 4 days
 10   
 ↔
 ↑17%
Lamivudine, 150 mg
single dose
 40 mg single dose
 18   
 ↔
(92.7-100.6%)
 ↑12%
(100.3-126.1%)
Nelfinavir, 750 mg
q8h for 56 days
 30 to 40 mg q12h
for 56 days
 8   
 ↔
 ↔



Table 6: Results of Drug Interaction Studies with Stavudine: Effects of Stavudine on Coadministered Drug Plasma AUC and Cmax Values
Drug  StavudineDosage  na    AUC of
 Coadministered 
 Drug
(95% CI) 		Cmax of
 Coadministered 
 Drug
(95% CI)
↔ indicates no change, or mean increase or decrease of greater then 10%.
a HIV-infected patients.
Didanosine, 100 mg
 q12h for 4 days
 40 mg q12h
for 4 days
 10   
 ↔
 ↔
Lamivudine, 150 mg 
 single dose
 40 mg single
dose
 18     
 ↔
(90.5-107.6%)
 ↔
(87.1-110.6%)
Nelfinavir, 750 mg
 q8h for 56 days
 30 to 40 mg q12h
for 56 days
 8   
 ↔
 ↔

INDICATIONS & USAGE



Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection (see Clinical Studies).









STAVUDINE CONTRAINDICATIONS




WARNINGS



1.      Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. PRECAUTIONS: Pregnancy

3. Neurologic Symptoms



2.     Hepatic Impairment and Toxicity







In vitro CLINICAL PHARMACOLOGY: Drug Interactions hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon and ribavirin


ADVERSE REACTIONS

4.      Pancreatitis


PRECAUTIONS






Immune Reconstitution Syndrome

Mycobacterium aviumPneumocystis jiroveci

INFORMATION FOR PATIENTS



(See Patient Information Leaflet .)
















DRUG INTERACTIONS



(see also CLINICAL PHARMACOLOGY )



In vitro in vitro WARNINGS


E. coli in vitroin vivoin vitroin vivo

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PREGNANCY




Pregnancy Category C

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WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.




NURSING MOTHERS



The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. mothers should be instructed not to breast-feed if they are receiving stavudine

PEDIATRIC USE







CLINICAL PHARMACOLOGY, Table 3

GERIATRIC USE







DOSAGE AND ADMINISTRATION: Dosage Adjustment

STAVUDINE ADVERSE REACTIONS



Adults







DOSAGE AND ADMINISTRATION




Table 7: Selected Clinical Adverse Events in Study AI455-019a

Percent (%)
Adverse Events Stavudineb
(40 mg twice daily)
(n=412) 		Zidovudine
(200 mg 3 times daily)
(n=402)
  Any severity, regardless of relationship to study drug.
 Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.
Headache
 54
 49
Diarrhea
 50
 44
Peripheral Neurologic Symptoms/Neuropathy
 52
 39
Rash
 40
 35
Nausea and Vomiting
 39
 44





Table 8: Selected Clinical Adverse Eventsa in START 1 and START 2 Studies 
Adverse Events Percent (%)
START 1 START 2
Stavudine +
 lamivudine +
 indinavir
 (n=100c) 		Zidovudine +
 lamivudine +
indinavir
(n=102) 		Stavudine +
didanosine +
indinavir
 (n=102c) 		Zidovudine +
lamivudine +
 indinavir
 (n=103)
A Any severity, regardless of relationship to study regimen.
B START 2 compared two triple-combination regimens in 205 treatment-naive patients.
Patients received either stavudine (40 mg twice daily) plus didanosine plus indinavir or
zidovudine plus lamivudine plus indinavir.
C Duration of stavudine therapy = 48 weeks.
Nausea
 43
 63
 53
 67
Diarrhea
 34
 16
 45
 39
Headache
 25
 26
 46
 37
Rash
 18
 13
 30
 18
Vomiting
 18
 33
 30
 35
 Peripheral Neurologic Symptoms/Neuropathy 8
 7
 21
 10











Table 9: Selected Adult Laboratory Abnormalities in Study AI455-019a,b

Percent (%)
Parameter Stavudine
 (40 mg twice daily) 
(n=412) 		Zidovudine
 (200 mg 3 times daily) 
 (n=402)
 Data presented for patients for whom laboratory evaluations were
   performed.
  Median duration of stavudine therapy = 79 weeks; median duration of
   zidovudine therapy = 53 weeks.
 ULN = upper limit of normal.
AST (SGOT) (less then5 x ULN)   
 11
 10
ALT (SGPT) (less then 5 x ULN) 
13
 11
Amylase (less then 1.4 x ULN)  
14
 13





Table 10: Selected Laboratory Abnormalities in START 1 and START 2 Studies
(Grades 3 to 4)
  Percent (%)
START 1 START 2
Parameter Stavudine +
 lamivudine +
 indinavir
 (n=100) 		Zidovudine +
 lamivudine +
 indinavir
 (n=102) 		Stavudine +
 didanosine +
 indinavir
 (n=102) 		Zidovudine +
 lamivudine +
 indinavir
 (n=103)
ULN = upper limit of normal.
Bilirubin (less then 2.6 x ULN)
7
 6
 16
 8
AST (SGOT) (less then 5 x ULN)
5
 2
 7
 7
ALT (SGPT) (less then 5 x ULN)
6
 2
 8
 5
GGT (less then 5 x ULN)
2
 2
 5
 2
Lipase (less then 2 x ULN)
6
 3
 5
 5
Amylase (less then 2 x ULN)
4
 less then 1
 8
 2




Table 11: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades)

Percent (%)
START 1 START 2
Parameter Stavudine +
 lamivudine +
 indinavir
 (n=100) 		Zidovudine +
 lamivudine +
 indinavir
 (n=102) 		Stavudine +
 didanosine +
 indinavir
 (n=102) 		Zidovudine +
 lamivudine +
 indinavir
 (n=103)
Total Bilirubin 
65
 60
 68
 55
AST (SGOT)
 42
 20
 53
 20
ALT (SGPT)
 40
 20
 50
 18
GGT
 15
 8
 28
 12
Lipase
 27
 12
 26
 19
Amylase
 21
 19
 31
 17






Body as a Whole PRECAUTIONS: Fat Redistribution

Digestive Disorders

Exocrine Gland Disorders WARNINGS

Hematologic Disorders

Liver WARNINGS

Metabolic Disorders

Musculoskeletal

Nervous System WARNINGS

Use with Didanosine- and Hydroxyurea-Based Regimens

WARNINGS  PRECAUTIONS

Pediatric Patients

PRECAUTIONS: Pediatric Use



OVERDOSAGE




DOSAGE & ADMINISTRATION





Adults







PEDIATRIC USE



CLINICAL PHARMACOLOGY
WARNINGS






Renal Impairment


Table 12: Recommended Dosage Adjustment for Renal Impairment
Creatinine Clearance(mL/min) Recommended Stavudine Capsules Dose
by Patient Weight
less then 60 kg greater then 60 kg
less then 50
 40 mg every 12 hours
 30 mg every 12 hours
26–50
 20 mg every 12 hours
 15 mg every 12 hours
10–25
 20 mg every 24 hours
 15 mg every 24 hours



Hemodialysis Patients



HOW SUPPLIED



Stavudine Capsules USP, 15 mg



Stavudine Capsules USP, 20 mg



Stavudine Capsules USP, 30 mg



Stavudine Capsules USP, 40 mg


Store at


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION














STAVUDINE

STAVUDINE

STAVUDINE

STAVUDINE CAPSULE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:49349-066(NDC:65862-047)
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
STAVUDINE STAVUDINE 40 mg

Inactive Ingredients

Ingredient Name Strength
cellulose, microcrystalline
SODIUM STARCH GLYCOLATE TYPE A POTATO
ANHYDROUS LACTOSE
MAGNESIUM STEARATE
GELATIN
SODIUM LAURYL SULFATE
titanium dioxide
FERRIC OXIDE YELLOW
FERROSOFERRIC OXIDE

Product Characteristics

Color Size Imprint Code Shape
orange 19 mm C;37 CAPSULE

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:49349-066-02 30 in 1 BLISTER PACK

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077672 2010-11-11


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