Sirolimus

• shake bottle well before use • measure only with dosing cup provided. Do not use dosing cup with other products. • dose as follows or as directed by a doctor • mL = milliliter

adults and children 12 years of age

and over

10 mL every 12 hours, not to exceed 20 mL in 24 hours

children 6 to under 12 years of age

5 mL every 12 hours, not to exceed 10 mL in 24 hours

children 4 to under 6 years of age

2.5 mL every 12 hours, not to exceed 5 mL in 24 hours

children under 4 years of age

do not use

2.1 Dosage in Adults

Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7 to 8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.1)]. The total dose of zolpidem tartrate tablets should not exceed 10 mg once daily immediately before bedtime.

The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

2.2 Special Populations

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of zolpidem tartrate tablets in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.1); Use in Specific Populations (8.5)].

2.3 Use with CNS Depressants

Dosage adjustment may be necessary when zolpidem tartrate tablets are combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].

2.4 Administration

The effect of zolpidem tartrate tablets may be slowed by ingestion with or immediately after a meal.

Sirolimus tablets are to be administered orally once daily, consistently with or without food [see DOSAGE AND ADMINISTRATION (2.4), CLINICAL PHARMACOLOGY (12.3)].

Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use. 

The initial dose of sirolimus tablets should be administered as soon as possible after transplantation. It is recommended that sirolimus tablets be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see DRUG INTERACTIONS (7.2)].

Frequent sirolimus tablets dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus tablets maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus tablets dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum sirolimus tablets dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

2.1 Patients at Low- to Moderate-Immunologic Risk

Sirolimus and Cyclosporine Combination Therapy

For de novo renal transplant patients, it is recommended that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range [see DOSAGE AND ADMINISTRATION (2.3)].

Sirolimus Following Cyclosporine Withdrawal

At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [see DOSAGE AND ADMINISTRATION (2.3)]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [see CLINICAL PHARMACOLOGY (12.3)].

2.2 Patients at High-Immunologic Risk

In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [see CLINICAL STUDIES (14.3)]. The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.

 

For patients receiving sirolimus with cyclosporine, sirolimus therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should thereafter be adjusted [see DOSAGE AND ADMINISTRATION (2.3)].

The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations [see DOSAGE AND ADMINISTRATION (2.3)]. Prednisone should be administered at a minimum of 5 mg/day. 

Antibody induction therapy may be used. 

2.3 Therapeutic Drug Monitoring

Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see DRUG INTERACTIONS (7)].

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters. 

When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range [see CLINICAL STUDIES (14), CLINICAL PHARMACOLOGY (12.3)]. Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL. 

The above recommended 24 hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable [see WARNINGS AND PRECAUTIONS (5.15), CLINICAL PHARMACOLOGY (12.3)]. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see REFERENCES (15)].

2.4 Patients with Low Body Weight

The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2.

2.5 Patients with Hepatic Impairment

It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the sirolimus loading dose [see CLINICAL PHARMACOLOGY (12.3)].

2.6 Patients with Renal Impairment

Dosage adjustment is not needed in patients with impaired renal function [see USE IN SPECIFIC POPULATIONS (8.7)].

2.1 Adult Patients

[See INDICATIONS AND USAGE (1.1) and CLINICAL PHARMACOLOGY (12.3)]

* DUE TO THE INDICATED ORGANISMS [see INDICATIONS AND USAGE ( 1.1)] Infection*
Recommended Dose/Duration of Therapy
Community-acquired pneumonia Pharyngitis/tonsillitis (second-line therapy) Skin/skin structure (uncomplicated)
500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5
Acute bacterial exacerbations of chronic obstructive pulmonary disease
500 mg once daily for 3 days 
OR 
500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5
Acute bacterial sinusitis
500 mg once daily for 3 days
Genital ulcer disease (chancroid)
One single 1 gram dose
Non-gonococcal urethritis and cervicitis
One single 1 gram dose
Gonococcal urethritis and cervicitis
One single 2 gram dose

Azithromycin tablets can be taken with or without food.

2.2 Pediatric Patients

1see dosing tables below for maximum doses evaluated by indication

* DUE TO THE INDICATED ORGANISMS [see INDICATIONS AND USAGE ( 1.2)] Infection* 
Recommended Dose/Duration of Therapy 
Acute otitis media 
30 mg/kg as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg/day on Days 2 through 5. 
Acute bacterial sinusitis 
10 mg/kg once daily for 3 days. 
Community-acquired pneumonia 
10 mg/kg as a single dose on Day 1 followed by 5 mg/kg once daily on Days 2 through 5. 
Pharyngitis/tonsillitis 
12 mg/kg once daily for 5 days. 

Azithromycin for oral suspension can be taken with or without food.

PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS, AND COMMUNITY-ACQUIRED PNEUMONIA(Age 6 months and above, [see USE IN SPECIFIC POPULATIONS (8.4)]) Based on Body Weight * Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established. OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen)*
Dosing Calculated on 10 mg/kg/day Day 1 and 5 mg/kg/day Days 2 to 5.
Weight
100 mg/5 mL
200 mg/5 mL


Kg
Lbs.
Day 1
Day 2 to 5
Day 1
Day 2 to 5
Total mL per Treatment Course
Total mg per Treatment Course
5
11
2.5 mL; 
(½ tsp)
1.25 mL;
(¼ tsp)


7.5 mL
150 mg
10
22
5 mL; 
(1tsp)
2.5 mL; 
(½ tsp)


15 mL
300 mg
20
44


5 mL; 
(1 tsp)
2.5 mL; 
(½ tsp)
15 mL
600 mg
30
66


7.5 mL; (1½ tsp)
3.75 mL; 
(¾ tsp)
22.5 mL
900 mg
40
88


10 mL; 
(2 tsp)
5 mL;
(1 tsp)
30 mL
1200 mg
50 and above
110 and above


12.5 mL; (2½ tsp)
6.25 mL; (1¼ tsp)
37.5 mL
1500 mg
* Effectiveness of the 5-day or 1-day regimen in pediatric patients with acute bacterial sinusitis has not been established. OTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen)*
Dosing Calculated on 10 mg/kg/day.
Weight
100 mg/5 mL
200 mg/5 mL


Kg
Lbs.
Days 1 to 3
Days 1 to 3
Total mL per
Treatment Course
Total mg per Treatment Course
5
11
2.5 mL; (1/2 tsp)

7.5 mL
150 mg
10
22
5 mL; (1 tsp)

15 mL
300 mg
20
44

5 mL (1 tsp)
15 mL
600 mg
30
66

7.5 mL (1½ tsp)
22.5 mL
900 mg
40
88

10 mL (2 tsp)
30 mL
1200 mg
50 and above
110 and above

12.5 mL (2 ½ tsp)
37.5 mL
1500 mg
OTITIS MEDIA: (1-Day Regimen)
Dosing Calculated on 30 mg/kg as a single dose.
Weight
200 mg/5 mL


Kg
Lbs.
1-Day Regimen
Total mL per Treatment Course
Total mg per Treatment Course
5
11
3.75 mL;(3/4 tsp)
3.75 mL
150 mg
10
22
7.5 mL;(1½ tsp)
7.5 mL
300 mg
20
44
15 mL;(3 tsp)
15 mL
600 mg
30
66
22.5 mL;(4½ tsp)
22.5 mL
900 mg
40
88
30 mL;(6 tsp)
30 mL
1200 mg
50 and above
110 and above
37.5 mL;(7½ tsp)
37.5 mL
1500 mg

The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, eight patients who vomited within 30 minutes of dosing were re-dosed at the same total dose.

Pharyngitis/Tonsillitis

The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. (See chart below.)

PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS(Age 2 years and above, [see USE IN SPECIFIC POPULATIONS (8.4)]) Based on Body Weight PHARYNGITIS/TONSILLITIS: (5-Day Regimen)
Dosing Calculated on 12 mg/kg/day for 5 days.
Weight
200 mg/5 mL


Kg
Lbs.
Day 1 to 5
Total mL per Treatment Course
Total mg per Treatment Course
8
18
2.5 mL; (½ tsp)
12.5 mL
500 mg
17
37
5 mL; (1 tsp)
25 mL
1000 mg
25
55
7.5 mL; (1½ tsp)
37.5 mL
1500 mg
33
73
10 mL; (2 tsp)
50 mL
2000 mg
40
88
12.5 mL; (2½ tsp)
62.5 mL
2500 mg

Constituting instructions for azithromycin oral suspension 300, 600, 900, 1200 mg bottles. The table below indicates the volume of water to be used for constitution:

Amount of water to be added 
Total volume after constitution (azithromycin content) 
Azithromycin concentration after constitution 
9 mL (300 mg) 
15 mL (300 mg) 
100 mg/5 mL 
9 mL (600 mg) 
15 mL (600 mg) 
200 mg/5 mL 
12 mL (900 mg) 
22.5 mL (900 mg) 
200 mg/5 mL 
15 mL (1200 mg) 
30 mL (1200 mg) 
200 mg/5 mL 

Shake well before each use. Oversized bottle provides shake space. Keep tightly closed.

After mixing, store suspension at 5° to 30°C (41° to 86°F) and use within 10 days. Discard after full dosing is completed.

Sirolimus tablets are to be administered orally once daily, consistently with or without food [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 

Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use. 

The initial dose of sirolimus tablets should be administered as soon as possible after transplantation. It is recommended that sirolimus tablets be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see Drug Interactions (7.2)]. 

Frequent sirolimus tablets dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus tablets maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus tablets dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus tablets loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum sirolimus tablets dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s). 

Two milligrams (2 mg) of sirolimus oral solution have been demonstrated to be clinically equivalent to 2 mg sirolimus tablets; hence, are interchangeable on a mg-to-mg basis. However, it is not known if higher doses of sirolimus oral solution are clinically equivalent to higher doses of sirolimus tablets on a mg-to-mg basis [see Clinical Pharmacology (12.3)].

2.1 Patients at Low- to Moderate-Immunologic Risk

Sirolimus Tablets and Cyclosporine Combination Therapy

For de novo renal transplant patients, it is recommended that sirolimus oral solution and tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus tablets equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range [see Dosage and Administration (2.3)].

Sirolimus Tablets Following Cyclosporine Withdrawal

At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus tablets dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [see Dosage and Administration (2.3)]. Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus tablets dose is increased [see Clinical Pharmacology (12.3)].

2.2 Patients at High-Immunologic Risk

In patients with high-immunologic risk, it is recommended that sirolimus tablets be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [see Clinical Studies (14.3)]. The safety and efficacy of this combination in high- immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.

For patients receiving sirolimus tablets with cyclosporine, sirolimus tablets therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus tablets should thereafter be adjusted [see Dosage and Administration (2.3)].

The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations [see Dosage and Administration (2.3)]. Prednisone should be administered at a minimum of 5 mg/day. 

Antibody induction therapy may be used.

2.3 Therapeutic Drug Monitoring

Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus tablets dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [see Drug Interactions (7)].

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus tablets therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters.

When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range [see Clinical Studies (14), Clinical Pharmacology (12.3)]. Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL.

The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable [see Warnings and Precautions (5.15), Clinical Pharmacology (12.3)]. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see References (15)].

2.4 Patients with Low Body Weight

The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2.

2.5 Patients with Hepatic Impairment

It is recommended that the maintenance dose of sirolimus tablets be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the sirolimus tablets loading dose [see Clinical Pharmacology (12.3)].

2.6 Patients with Renal Impairment

Dosage adjustment is not needed in patients with impaired renal function [see Use in Specific Populations (8.7)].