Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate (Page 6 of 12)

8.2 Lactation

Risk Summary: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Efavirenz: EFV has been shown to pass into human breast milk. There is no information available on the effects of EFV on the breastfed infant, or the effects of EFV on milk production.

Lamivudine: 3TC is present in human milk. Samples of breast milk obtained from 20 mothers receiving 3TC monotherapy, 300 mg twice daily (2 times the dose in efavirenz, lamivudine and tenofovir disoproxil fumarate tablets), had measurable concentrations of 3TC. There is no information on the effects of 3TC on the breastfed infant, or the effects of 3TC on milk production.

Tenofovir Disoproxil Fumarate: Based on published data, tenofovir has been shown to be present in human breast milk (see Data). It is not known if tenofovir affects milk production or has effects on the breastfed child.

Because of the potential for (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving efavirenz, lamivudine and tenofovir disoproxil fumarate.

Data: Tenofovir Disoproxil Fumarate: In a study of 50 HIV-uninfected, breastfeeding women on a tenofovir-containing regimen initiated between 1 and 24 weeks postpartum (median 13 weeks), tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. There were no serious adverse events in mothers or infants.

8.3 Females and Males of Reproductive Potential

Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz, lamivudine and tenofovir disoproxil fumarate [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Pregnancy Testing:
Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz, lamivudine and tenofovir disoproxil fumarate.

Contraception: Females of reproductive potential should use effective contraception during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate and for 12 weeks after discontinuing efavirenz, lamivudine and tenofovir disoproxil fumarate due to the long half-life of EFV. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness [see Drug Interactions (7.5)].

8.4 Pediatric Use

The safety and effectiveness of efavirenz, lamivudine and tenofovir disoproxil fumarate as a fixed-dose tablet in pediatric patients infected with HIV-1 and weighing at least 35 kg have been established based on clinical studies using the individual components (efavirenz, lamivudine, and tenofovir disoproxil fumarate).

8.5 Geriatric Use

Clinical studies of efavirenz, lamivudine and tenofovir disoproxil fumarate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of 3TC in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Efavirenz, lamivudine and tenofovir disoproxil fumarate is not recommended for patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis because it is a fixed-dose combination formulation that cannot be adjusted [see Dosage and Administration (2.3)].

8.7 Hepatic Impairment

Efavirenz, lamivudine and tenofovir disoproxil fumarate is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz, lamivudine and tenofovir disoproxil fumarate without any adjustment in dose [see Dosage and Administration (2.4),Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Efavirenz: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
Treatment of overdose with EFV should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

Lamivudine: There is no known specific treatment for overdose with 3TC. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required because a negligible amount of 3TC 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 3TC overdose event.

Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of TDF 300 mg is available.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

Efavirenz, lamivudine and tenofovir disoproxil fumarate is a fixed-dose combination tablet for oral administration. Each film coated tablet contains efavirenz USP 400 mg, lamivudine USP 300 mg and tenofovir disoproxil fumarate 300 mg equivalent to tenofovir disoproxil 245 mg. Each tablet contains the following inactive ingredients: croscarmellose sodium, ferric oxide yellow, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, talc and titanium dioxide.

Efavirenz: Efavirenz (EFV) is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H -3,1-benzoxazin-2-one. Its molecular formula is C14 H9 ClF3 NO2 and its structural formula is:

efavirenz-structure

Efavirenz USP is a white to off white powder with a molecular mass of 315.67. It is soluble in methanol and practically insoluble in water (< 10 microgram/mL).

Lamivudine: Lamivudine (also known as 3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV.The chemical name of lamivudine is (-)-1-[(2R ,5S)-2-(Hydroxy methyl)-1,3-oxathiolan-5-yl]cytosine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8 H11 N3 O3 S and a molecular weight of 229.26 g per mol. It has the following structural formula:

lamivudine-structure

Lamivudine USP is a white or almost white powder and is soluble in water.

Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate (TDF) (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′ -monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

The chemical name of tenofovir disoproxil fumarateis 9-[(R)-2- [[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19 H30 N5 O10 P•C4 H4 O4 and a molecular weight of 635.52. It has the following structural formula:

tenofovir-structure

Tenofovir disoproxil fumarate is a white to off white powder freely soluble in dimethyl formamide, soluble in methanol and slightly soluble in water at 25°C. It has a partition coefficient (log p) of 0.75.

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