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Intron A Rebetol

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Intron A - Rebetol

INDICATIONS

REBETOL (ribavirin, USP) Capsules is indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy.

Description of Clinical Studies

Previously Untreated Patients

Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL Capsules 1200 mg/day (1000 mg/day for patients weighing £75kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24 week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in Table 2 .

Table 2. Virologic and Histologic Responses: Previously Untreated Patients*

 

US Study

International Study

 

24 weeks of treatment

48 weeks of treatment

24 weeks of treatment

48 weeks of treatment

 

INTRON A plus REBETOL

(N=228)

INTRON A plus Placebo

(N=231)

INTRON A plus REBETOL

(N=228)

INTRON A plus Placebo

(N=225)

INTRON A plus REBETOL

(N=265)

INTRON A plus REBETOL

(N=268)

INTRON A plus Placebo

(N=266)

Virologic Response

-Responder 1

-Nonresponder

-Missing Data

65(29)

147(64)

16(7)

13(6)

194(84)

24(10)

85(37)

110(48)

33(14)

27(12)

168(75)

30(13)

86(32)

158(60)

21(8)

113(42)

120(45)

35(13)

46(17)

196(74)

24(9)

Histologic Response

-Improvement2

-No improvement

-Missing Data

102(45)

77(34)

49(21)

77(33)

99(43)

55(24)

96(42)

61(27)

71(31)

65(29)

93(41)

67(30)

103(39)

85(32)

77(29)

102(38)

58(22)

108(40)

69(26)

111(41)

86(32)


* Number (%) of Patients

1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

2. Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ³2 points.

Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of REBETOL/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among patients with HCV Genotype 1 treated with REBETOL/INTRON A therapy who achieved HCV RNA below the detection limit of the research based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24 week treatment group. There was no observed increase in response rates for patients with HCV non-genotype 1 randomized to REBETOL/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Patients

Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL 1200 mg/day (1000 mg/day for patients weighing £75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy

follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% caucasian, mean Knodell score 6.6, and 56% genotype 1).

Study results are summarized in table 3 .

Table 3. Virologic and Histologic Responses: Relapse Patients*

 

US Study

International Study

 

INTRON A plus REBETOL

N=77

INTRON A plus Placebo

N=76

INTRON A plus REBETOL

N=96

INTRON A plus Placebo

N=96

Virologic Response

-Responder1

-Nonresponder

-Missing Data

33(43)

36(47)

8(0)

3(4)

66(87)

7(9)

46(48)

45(47)

5(5)

5(5)

91(95)

0(0)

Histologic Response

-Improvement2

-No improvement

-Missing Data

38(49)

23(30)

16(21)

27(36)

37(49)

12(16)

49(51)

29(30)

18(19)

30(31)

44(46)

22(23)


* Number (%) of Patients.

1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

2. Defined as post treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ³2 points.

Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.

DOSAGE AND ADMINISTRATION

INTRON A Injection should be administered subcutaneously and Rebetol Capsules should be administered orally (see Table 6).

The recommended dose of REBETOL Capsules depends on the patients body weight. The recommended doses of Rebetol and INTRON A are given in Table 6.

The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen (see

INDICATIONS

Description of Clinical Studies and ADVERSE REACTIONS). After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

In patients who relapse following interferon therapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.

Table 6. Recommended Dosing

Body weight REBETOL Capsules INTRON A Injection
£ 75 kg 2 x 200 mg capsules Am,

3 x 200 mg capsules PM

daily p.o.

3 million IU 3 times weekly s. c.
> 75 kg 3 x 200 mg capsules AM,

3 x 200 mg capsules PM,

daily p.o.

3 million IU 3 times weekly s. c.


REBETOL may be administered without regard to food, but should be administered in a consistent manner. (See CLINICAL PHARMACOLOGY.)

Dose Modifications ( TABLE 7 )

In clinical trials, approximately 26% of patients required modification of their dose of REBETOL Capsules, INTRON A Injection, or both agents. If severe adverse reactions or laboratory abnormalities develop during combination REBETOL/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, REBETOL/INTRON A therapy should be discontinued. REBETOL/INTRON A therapy should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped. (See WARNINGS. )

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ³2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination REBETOL/INTRON A therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL dose reduced to 600 mg daily (1 x 200 mg capsule AM , 2 x 200 mg capsules PM ). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from REBETOL/INTRON A therapy. (See WARNINGS.)

It is recommended that a patient who experiences moderate depression (persistent low mood, loss of interest, p.o. self image, and/or hopelessness) have his/her INTRON A dose temporarily reduced and/or be considered for medical therapy. A patient experiencing severe depression or suicidal ideation/attempt should be discontinued from REBETOL/INTRON A therapy and followed closely with appropriate medical management. (See WARNINGS.)

TABLE 7. Guidelines for Dose Modifications

  Dose Reduction *

REBETOL - 600 mg daily

INTRON A - 1.5 million IU TIW

Permanent Discontinuation of Treatment

REBETOL and INTRON A

Hemoglobin <10 g/dL (REBETOL) <8.5 g/dL
  Cardiac History Patients only. ³2 g/dL decrease during any 4-week period during treatment

(REBETOL/INTRON A)

Cardiac History Patients only. <12 g/dL after 4 weeks of dose reduction
White blood count <1.5 x 109 /L (INTRON A) <1.0 x 109 /L
Neutrophil count <0.75 x 109 /L (INTRON A) <0.5 x 109 /L
Platelet count <50 x 109 /L (INTRON A) <25 x 109 /L


* Study medication to be dose reduced is shown in parenthesis

Administration of INTRON A Injection

At the discretion of the physician, the patient may self-administer the INTRON A. (See illustrated MEDICATION GUIDE for instructions.)

The Intron A Injection is supplied as a clear and colorless solution. The appropriate INTRON A dose should be withdrawn from the vial or set on the multidose pen and injected subcutaneously. After administration of INTRON A Injection, it is essential to follow the procedure for proper disposal of syringes and needles. (See MEDICATION GUIDE for detailed instructions.)

Vial/Pen Label Strength Fill Volume Concentration
3 million IU vial 0.5 mL 3 million IU/0.5 mL
18 million IU multidose vial† 3.8 mL 3 million IU/0.5 mL
18 million IU multidose pen†† 1.5 mL 3 million IU/0.2 mL


†This is a multidose vial which contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL in order to provide the delivery of six 0.5-mL doses, each containing 3 million IU of interferon alfa-2b, recombinant (for a label strength of 18 million IU).

†† This is a multidose pen which contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to provide the delivery of six 0.2-mL doses, each containing 3 million IU of interferon alfa-2b, recombinant (for a label strength of 18 million IU).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INTRON A Injection may be administered using either sterilized glass or plastic disposable syringes.

Stability

INTRON A Injection provided in vials is stable at 35o C(95o F) for up to 7 days and at 30o C (86o F) for up to 14 days. INTRON A Injection provided in a multidose pen is stable at 30o C (86o F) for up to 2 days. The solution is clear and colorless.

HOW SUPPLIED

REBETOL 200-mg Capsules are white, opaque capsules with REBETOL, 200 mg, and the Schering Corporation logo imprinted on the capsule shell; the capsules are packaged in blisters.

INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.

INTRON A Injection and REBETOL Capsules are available in the following combination package presentations:

Each REBETRON Combination Package Consists of:
For Patients £75 kg A box containing 6 vials of Intron A Injection (3 million IU in 0.5 mL per vial) and 6 syringes and alcohol swabs. Two boxes containing 35 Rebetol Capsules each for a total of 70 capsules (5 capsules per blister card). (NDC 0085-241-02)
one 18 million IU multidose vial of Intron A Injection (NDC 0085-1236-02) (22.8 million IU per 3.8 mL; 3 million IU/0.5 mL) and 6 syringes and alcohol swabs. Two boxes containing 35 Rebetol Capsules each for a total of 70 capsules (5 capsules per blister card).
One 18 million IU INTRON A Injection multidose pen (NDC 0085-1258-02) (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL) and 6 disposable needles and alcohol swabs. Two boxes containing 35 Rebetol Capsules each for a total of 70 capsules (5 capsules per blister card).
For Patients >75 kg A box containing 6 vials of Intron A Injection (3 million IU in 0.5 mL per vial) and 6 syringes and alcohol swabs. Two boxes containing 42 Rebetol Capsules each for a total of 84 capsules (6 capsules per blister card). (NDC 0085-1241-01)
one 18 million IU multidose vial of Intron A Injection (NDC 0085-1236-01) (22.8 million IU per 3.8 mL; 3 million IU/0.5 mL) and 6 syringes and alcohol swabs. Two boxes containing 42 Rebetol Capsules each for a total of 84 capsules (6 capsules per blister card).
One 18 million IU INTRON A Injection multidose pen (NDC 0085-1258-01) (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL) and 6 disposable needles and alcohol swabs. Two boxes containing 42 Rebetol Capsules each for a total of 84 capsules (6 capsules per blister card).
For REBETOL Dose Reduction A box containing 6 vials of Intron A Injection (3 million IU in 0.5 mL per vial) and 6 syringes and alcohol swabs. One box containing 42 Rebetol Capsules (6 capsules per blister card). (NDC 0085-1241-03)
one 18 million IU multidose vial of Intron A Injection (NDC 0085-1236-03) (22. million IU per 3.8 mL; 3 million IU/0.5 mL) 8 and 6 syringes and alcohol swabs. One box containing 42 Rebetol Capsules (6 capsules per blister card).
One 18 million IU INTRON A Injection multidose pen (NDC 0085-1258-03) (22.5 million IU per 1.5 mL; 3 million IU/0.2 mL) and 6 disposable needles and alcohol swabs. One box containing 42 Rebetol Capsules (6 capsules per blister card).

Storage Conditions

Store the REBETOL Capsules plus INTRON A Injection combination package refrigerated between 2ºC and 8ºC (36ºF and 46º F).

When separated, the individual carton of REBETOL Capsules should be stored refrigerated between 2º C; and 8ºC (36ºand 46ºF) or at 25ºC (77ºF); excursions are permitted between 15 and 30ºC (59º and 86ºF).

When separated, the individual carton or vial of INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2º and 8ºC (36º and 46ºF).

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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