HEALTH 2000 INC. EXPANDING PARTNERSHIPS IN HEALTH CARE............

1. ROUTE OF ADMINISTRATION

Oral

DOSAGE AND ADMINISTRATION

The recommended oral dose of Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet for adults and adolescents (at least 12 years of age) is one tablet (containing 150 mg of lamivudine and 300 mg of zidovudine ) twice daily with or without food .

Dose adjustment
Because it is a fixed dose combination, Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet should not be prescribed for patients requiring dosage adjustments ,such as those with reduced renal function(creatinine clearance ,=50 mL/min),those with low body weight(<50 kg or 110 lb) or those experiencing dose-limiting adverse events .

2. THERAPEUTIC / DIAGNOSTIC CLAIMS

Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet is indicated for the treatment of HIV infection.

3. DESCRIPTION OF DOSAGE FORM

Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet is a combination of two drugs commonly used in the management of HIV infection. Both lamivudine and zidovudine belongs to the nucleoside analogue class of antiretroviral drugs. Both drugs act by inhibiting the reverse transcriptase enzyme of HIV, and by terminating the growth of the DNA chain. Lamivudine in combination with zidovudine has been shown to have synergistic antiretroviral activity.
Each tablet of Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet contains half of the commonly prescribed daily doses of both lamivudine and zidovudine. With the availability of this combination tablet, patients may be better able to adhere to complex drug treatment regimens, thereby enhancing compliance.

Warnings and Precautions

Since Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet is a fixed-dose combination of lamivudine and zidovudine, it should ordinarily not be administered concomitantly with either lamivudine or zidovudine.
The complete prescribing information for all agents being considered for use with Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet should be consulted before combination therapy with Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet is initiated.

BONE MARROW SUPPRESSION
Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet should be used with caution in patients who have bone marrow
compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin < 9.5 g/dl (See Side Effects).
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet . For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended.

LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS
Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including zidovudine and lamivudine. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors.Caution should be exercised when administering Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet to any patient, and particularly to those with known risk factors for liver disease. Treatment with Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

PROLONGED MYOPATHY
Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine and therefore may occur with therapy with Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet.

PATIENTS WITH HIV AND HEPATITIS B VIRUS COINFECTION
In clinical trials and postmarketing experience, some patients with HIV
infection who have chronic liver disease due to hepatitis B virus infectionexperienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine. Consequences may be more severe in patients with decompensated liver disease.

DRUG INTERACTIONS
Coadministration of ganciclovir, interferon-a, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.

IMPAIRED RENAL FUNCTION
Reduction of the dosages of lamivudine and zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance < 50 ml/min should not receive Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet.

PREGNANCY
Category C. There are no adequate and well-controlled studies of this combination in pregnant women. Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet should be used during pregnancy only if the potential benefits outweigh the risks.

LACTATION
It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection.
Zidovudine is excreted in breast milk. No data are available on this combination or lamivudine. Therefore, there is a potential for adverse effects in nursing infants. Mothers should be instructed not to breast-feed if they are receiving Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet.

PAEDIATRICUSE
Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet should not be administered to paediatric patients less than 12 years of age because it is a fixed-dose combination that cannot be adjusted for this patient population.

OTHERS
Reduction of doses of lamivudine is recommended for patients with low body weight (less than 50 kg or 110 lb). Therefore patients with low body weight should not receive Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet.

4. CONTRAINDICATIONS

Health 2000 Lamivudine 150 mg + Zidovudine 300 mg tablet tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the product.

5. SIDE EFFECTS

The most commonly observed side effects during clinical trials were headache, malaise and fatigue, nausea, vomiting, diarrhoea, anorexia, fever/chills, neuropathy, insomnia, dizziness, nasal signs and symptoms, cough, musculoskeletal pain and neutropenia

6. TOXIC EFFECT:

Lamivudine
Short-term studies with either lamivudine or the racemate, BCH189 demonstrated that high dose levels were well tolerated in the mouse, rat, dog and marmoset following oral, and/or i.v. administration. Subchronic 90 day studies
have been completed in the rat doses up to 2000 mg/kg b.i.d. (i.e. 4000 mg/kg/day) produced only minor changes in hematological, clinical chemistry and urine analysis profiles. In the dog a dose of 1500 mg/kg b.i.d. produced moderate neutropenia and a reduction in red cell parameters. At this dose, one female dog died and two others were killed in extremis after 4-6 weeks of dosing, the cause of death could not be established but the decline in general state of health appeared to be triggered by treatment-induced inappetence. The remaining three females in this dose group survived to the end of the study and apart from hematologic changes showed no evidence of target organ effects. At the intermediate dose of 260 mg/kg b.i.d. the only significant findings were very minor changes in the red cell parameters and clinical chemistry measurements. Long-term studies (6 month in rat and 12 month in dog) are in progress, it should be noted that the dog study has progressed to week 15 with no recurrence of the mortalities seen in the 90 day study.
In a combination study in the mouse, there are no evidence of synergistic hematotoxicity when lamivudine (180, 600 or 2000 mg/kg/day) was coadministered with AZT (150mg/kg/day) for 30 days.
Organogenesis studies have indicated that lamivudine has no teratogenic potential in the rat (doses up to 2000 mg/kg b.i.d.) or the rabbit (up to 500 mg/kg b.i.d.) Some evidence of early embryo toxicity was seen in the rabbit at dose levels of 20 mg/kg b.i.d and above, but there was no indication of its effect in the rat.
In genetic toxicology tests, lamivudine, like many other nucleoside analogs, has shown evidence of weak activity in vitro cytogenic assays (at 100 mcg/ml and above) and the mouse lymphoma TK assay (at 1000 mcg/ml and above). However, no evidence of genotoxic activity was seen when the racemate (BCH 189) was examined in the rat bone marrow micronucleus test and the rat liver UDS test using doses of up to 600 mg/kg by the I.V. route. Negative results have also been obtained in an in vitro cell transformation assay using Balb/3T3 cells.