FORM DA -1/88

APPLICATION FORM FOR REGISTRATION OF DRUGS

(WHICH ARE INCLUDED IN MONOGRAPH IN BP/BPC/USP-NF/INT. PH. AND
ALREADY INTRODUCED IN BANGLADESH)

1. Name & Address of the Manufacturer : Veritas Pharmaceuticals Ltd.

2. Manufacturing License No.
3. Name of the Drug
4. Product Data Sheet : Please see Annexure -I (enclosed)
5. Technical Data Sheet : Please see Annexure -II (enclosed)
6. a) Number of Manufacturers already :
manufacturing the product in Bangladesh
b) Estimated market of this product/ :
product group in Bangladesh
7. a) Proposed maximum retail price
b) i) Estimated price per dose
ii) Estimated price per day treatment
iii) Cost for the recommended course of
treatment
8. For Locally Manufacturing Drugs :
Particulars of Production Manager and
Quality Assurance Manager
9. Information regarding imported Drugs
10. Date of submission
11. Additional information (if any)
Muradpur, Vannara, Mouchak,
Kaliakoir, Gazipur
: a) Biological : 288
b) Non-biological : 492
: a) Generic name -
Lamivudine USP 150mg + Nevirapine USP
200mg + Zidovudine USP 300mg Tablet
: b) Brand name –
To be submitted at the time of inclusion
About 10 manufacturers
1 million (approx.) Tablets are consumed per year
: To be submitted at the time of inclusion.
: To be submitted at the time of inclusion.
: Depends on Physician’s advice.
: Depends on Physician’s advice.
Please see Annexure III (enclosed)
: Not applicable.
:
: None

Annexure I

4. PRODUCT DATA SHEET

Composition

Each tablet contains Lamivudine USP 150mg + Nevirapine USP 200mg + Zidovudine USP 300
mg .
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Descriptions

Lamivudine, Nevirapine and Zidovudine Tablets for Oral Suspension are for oral administration.
Each scored tablet contains 30 mg of lamivudine USP, 50 mg of nevirapine USP and 60 mg of
zidovudine USP. The inactive ingredients are acesulfame potassium, aspartame, colloidal silicon
dioxide, ferric oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose,
orange flavor, povidone, and sodium starch glycolate.

Lamivudine and zidovudine are synthetic nucleoside analogues and nevirapine is a non-nucleoside
reverse transcriptase inhibitor with activity against HIV.

Mode of Action

The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA
chain termination after incorporation of the nucleotide analogue. 3TC-TP is a weak inhibitor of
cellular DNA polymerases α, β, and γ. Nevirapine: Nevirapine is a non-nucleoside reverse
transcriptase inhibitor (NNRTI) of HIV-1.

Indications and Uses

Lamivudine, Nevirapine, and Zidovudine Tablets is indicated alone as a complete regimen or in

combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1
(HIV-1) infection in adults and pediatric patients weighing at least 35 kg.

Additional important use regarding the use of nevirapine, a component of Lamivudine, Nevirapine,
and Zidovudine Tablets, for the treatment of HIV-1 infection:

 Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled

trials, Lamivudine, Nevirapine, and Zidovudine Tablets is not recommended to be initiated,
unless the benefit outweighs the risk in:
o adult females with CD4 + cell counts greater than 250 cells per mm 3 or
o adult males with CD4 + cell counts greater than 400 cells per mm 3

Dosage and Administrations

Adults and Pediatric Patients Weighing at Least 35 kg

Lead-in Period (First 14 days of dosing)

One lamivudine, nevirapine, and zidovudine fixed-dose tablet (containing 150 mg of lamivudine,
200 mg of nevirapine, and 300 mg of zidovudine) taken orally once daily followed by a daily oral
dose of lamivudine 150 mg and zidovudine 300 mg 12 hours later.

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Maintenance (After 14 days of dosing)

If the initial 14 days of dosing is tolerated without any incidence of rash, the recommended
maintenance dose is one lamivudine, nevirapine, and zidovudine fixed-dose tablet (containing 150
mg of lamivudine, 200 mg of nevirapine, and 300 mg of zidovudine) taken orally twice daily.

Lamivudine, Nevirapine, and Zidovudine Tablets can be taken with or without food.

Dosage Forms and Strengths

Lamivudine, Nevirapine, and Zidovudine Tablets contain 150 mg of lamivudine, 200 mg of
nevirapine, and 300 mg of zidovudine. The tablets are white to off-white colored, capsule shaped,
bevelled edged, biconvex, film-coated, debossed with “I” on one side and “47” on other side.

Contraindications

Lamivudine, Nevirapine, and Zidovudine Tablets are contraindicated:

 in patients with a previously hypersensitivity reaction to lamivudine, nevirapine, or

zidovudine,
 in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic
impairment [see Warnings and Precautions and Use in Specific Populations ].
 for use as part of occupational and non-occupational post-exposure prophylaxis (PEP)
regimens

Side-effects
 headache.
 diarrhea.
 heartburn.
 difficulty falling asleep or staying asleep.
 depression.
 stuffy nose.
 cough.
 joint pain.

Precautions & warnings

Hepatotoxicity and Hepatic Impairment

Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic
hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine,
a component of lamivudine, nevirapine, and zidovudine. tablets. In controlled clinical trials,
symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects
who received nevirapine and 1% of subjects in control groups.

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The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of
therapy. The risk continued to be greater in the nevirapine groups compared to controls through 18
weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases,
subjects presented with nonspecific, prodromal signs or symptoms of fatigue, malaise, anorexia,
nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum
transaminase levels. Rash was observed in approximately half of the subjects with symptomatic
hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events.
Some events, particularly those with rash and other symptoms, have progressed to hepatic failure
with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged
partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients
experiencing skin and/or liver reactions associated with nevirapine use. Hepatitis/hepatic failure may
be associated with signs of hypersensitivity which can include severe rash or rash accompanied by
fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial
edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. Patients with signs
or symptoms of hepatitis must be advised to discontinue Lamivudine, Nevirapine, and Zidovudine
Tablets and immediately seek medical evaluation, which should include liver enzyme tests.

The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and
laboratory monitoring of patients is required to detect potentially life-threatening hepatic events. The
optimal frequency of monitoring during this time period has not been established. Some experts
recommend clinical and laboratory monitoring more often than once per month, and in particular,
include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-
dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should
continue throughout nevirapine treatment.

Drug Interactions

Lamivudine:

When administered concomitantly, no change in dose of trimethoprim (TMP) 160

mg/sulfamethoxazole (SMX) 800 mg or lamivudine is recommended. There is no information
regarding
the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat
PCP.

Nevirapine:

Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6.

Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by
these
enzyme systems may have lower than expected plasma levels when co-administered with nevirapine

Zidovudine:
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Coadministration of ganciclovir, interferon alfa, and other bone marrow suppressive or
cytotoxic agents may increase the hematologic toxicity of zidovudine. Concomitant use of
zidovudine
with stavudine should be avoided since an antagonistic relationship with zidovudine has been
demonstrated in vitro. In addition, concomitant use of zidovudine with doxorubicin or ribavirin
should be
avoided because an antagonistic relationship with zidovudine has been demonstrated in vitro.

Warnings
Zidovudine, one of the three active ingredients in Lamivudine, Nevirapine, and Zidovudine Tablets,
has
been associated with hematologic toxicity including neutropenia and severe anemia, particularly in
patients with advanced Human Immunodeficiency Virus 1 (HIV-1) disease.
Prolonged use of zidovudine has been associated with symptomatic myopathy.
Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported with the
use
of nucleoside analogues alone or in combination, including lamivudine, zidovudine, and other
antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or
pronounced hepatotoxicity occur .

Acute exacerbations of Hepatitis B have been reported in patients who are co-infected with Hepatitis
B
Virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of Lamivudine,

Nevirapine, and Zidovudine Tablets. Hepatic function should be monitored closely with both clinical

and laboratory follow-up for at least several months in patients who discontinue Lamivudine,
Nevirapine, and Zidovudine Tablets and are co-infected with HIV-1 and HBV. If appropriate,
initiation
of anti-hepatitis B therapy may be warranted.

Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has

been reported in patients treated with nevirapine, one of the three active ingredients in Lamivudine,
Nevirapine, and Zidovudine Tablets. In some cases, patients presented with non-specific prodromal
signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated
with
rash. Female gender and higher CD4+ cell counts at initiation of therapy place patients at increased
risk;
women with CD4+ cell counts >250 cells/mm3, including pregnant women receiving nevirapine in
combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk.
However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4+ cell
counts
and at any time during treatment. Patients with signs or symptoms of hepatitis, or with increased
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transaminases combined with rash or other systemic symptoms, must discontinue Lamivudine,
Nevirapine, and Zidovudine Tablets seek medical evaluation immediately (see Warnings).

Over dosage

There is no known specific treatment for overdose with lamivudine, zidovudine, or nevirapine. If
overdose occurs, the patient should be monitored and standard supportive treatment applied as
required.

Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis,
continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if
continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Zidovudine: Acute overdoses of zidovudine have been reported in pediatric patients and adults.
These involved exposures up to 50 grams. No specific symptoms or signs have been identified
following acute overdosage with zidovudine apart from those listed as adverse events such as
fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3’-azido-
3’-deoxy-5’-O-b-D-glucopyranuronosylthymidine (GZDV), is enhanced.

Nevirapine: Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15
days have been reported. Patients have experienced events including edema, erythema nodosum,
fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight
decrease. All events subsided following discontinuation of nevirapine.

Storage

Store the tablets at room temperature, between 59° to 86°F (15° to 30°C).
Keep nevirapine and all medicines out of the reach of children.

Package Quantities

Lamivudine USP + Nevirapine USP + Zidovudine USP Tablet : Tablets in blister pack 10 s, 20 s,
30 s, 60 s, 100 s. or HDPE Container 10 s, 20 s, 30 s, 60 s, 100 s.

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 Annexure II

5. TECHNICAL DATA

a) Composition : Each tablet contains

Active Substance Specification Quantity Overage

s
Lamivudine USP 150 mg 1%
Nevirapine Hemihydrates USP 206.0 mg
(Equ. to 200 mg
Nevirapine)
Zidovudine USP 300 mg

Excipients

Microcrystalline Cellulose BP 105.00 mg

Starch BP 50.00 mg
Povidon K 30 BP 2.00 mg
Magnesium Stearate BP 1.00 mg
Sodium starch Glycolate BP 5.00mg

Coating Materials
Hypromellose 6 CPS USP 8.00 mg
Polyethyleneglycol 6000 BP 0.610 mg
Titanium Dioxide BP 0.610 mg
Suset Yellow Ph. Grad 3.00 mg

b) Manufacturing Process
Step-1: Weigh accurately Lamivudine, Nevirapine,Zidovudine, Sodium Starch Glycolate,
Microcrystalline Cellulose and starch Sieve through 30 mesh and mix For 10 minutes.

Step-2: Make binding solution of Povidone K 30 with required amount of distilled

Water, transfer to Step-1and kneads until to make a good granulating point.
Step-3: Dry the kneaded mass at 600C - 700C until LOD comes down to 1.50% - 2.00%. Sieve
the dried granules through 20 meshes.
Step-4: After Q.A approval compress into tablets using appropriate tool.

Step-5: Compressed tablet after QA approval are ready for coating

Film Coating
Step-6: Mix all ingredients homogeneously to make a smooth suspension.
Step-7: Spray coats the suspension on the tablets using a Film coating system.

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 Packing:
Step-8: tablets after QA approval are packed in Alu – Alu blister strips.
Step-9: Blister strips are further packed in printed cartons 10 s, 20 s, 30 s, 60 s, 100 s.
HDPE Container 10 s, 20 s, 30 s, 60 s, 100 s.

c) Control data for Active Substances : As indicated under specification in 5 a).

d) Control data for Excipients : As indicated under specification in 5 a).

e) Control data for finished product

Appearance : Sunset yellow Color, Oval shaped coated tablet

with, one side engraved with “V” and other side
break line tablet.
Average weight(mg) : Approx. 813.0 mg
Disintegration time : Not more than 30 minutes
Dissolution : Not less than 80% within 30 minutes
Assay (Lamivudine) : 90% to 110% of the label claim.
Assay (Nevirapine) : 90% to 110% of the label claim.
Assay (Zidovudine) : 90% to 110% of the label claim.
Claim : (Lamivudine 150.0 mg) : 135.0 mg – 165.0 mg
Claim : (Nevirapine 200.0mg) : 180.0 mg – 220.0 mg
Claim : (Zidovudine 300.0mg) : 270.0 mg – 330.0 mg

f) Stability data : Will be submitted at the time of inclusion.

g) Proposed shelf life : Two years from the date of manufacturing.

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 Annexure III

8. PARTICULARS OF PRODUCTION MANAGER AND QA MANAGER

Plant Manager:

1. Full Name Md. Didarul Alam

2. Qualification M. Pharm

3. Date of joining to Veritas Pharma Ltd. 06th October 2020

4. Total Experience 18 Years

5. Registration Number A-2406

6. Signature

7. Date

QA In-Charge:

1. Full Name Md. Tawhidunnabi

2. Qualification M. Pharm

3. Date of joining to Veritas Pharma Ltd. 11th July 2019

4. Total Experience 06 Years

5. Registration Number A-12767

6. Signature

7. Date

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