Objectives: After attending this lecture, reading the assigned material, and studying your notes, you should be able to:

1. Describe the course of infection in a patient exposure to the Human immunodeficiency virus type 1 (HIV-1).

2. Discuss the risk factors for exposure, and the nodes of transmission of HIV-1.

3. Describe the common serological tests used to detect HIV-1 and laboratory tests used to diagnose patients with HIV/AIDS.

4. Describe the common serological tests used to detect HIV-1 and laboratory tests used to monitor patients with HIV/AIDS.

5. Describe how to monitor and counsel a patient receiving any of the NRTIs, NNRTIs, and PIs.

6. Describe recommended prophylactic and treatment options in patients with HIV.

7. Discuss the concerns associated with the currently recommended HIV treatment regimens

8. Devise a rational prophylactic plan an HIV patient with any of the opportunistic infections discussed in class

9. Devise a rational treatment plan an HIV patient with any of the opportunistic infections discussed in class.

Required Reading:

Carpenter CCJ, Fischl MA, Hammer SM et al. Antiretroviral Therapy for HIV infection in 1997, updated recommendations of the international AIDS society-USA panel. JAMA 1997;277:1962-1969.

PI Perspective July 1997: 3-6

Deeks SG, Smith M, Holodniy M, and Kahn JO. HIV-1 protease inhibitors: a review for clinicians. JAMA 1997;277:145-153. ]

Pharmacotherapy, A Pathophysiologic Approach. 3rd edition. Dipiro JT, Talbert RL, Yee GC. Et al, eds. Chapter 117.

I. Introduction

A. Terminology

• HIV
• AIDS
• PLWHIV
• PLWA
• HIV challenged

B. General Facts about AIDS

1. Initially recognized in late 1970's, but not defined as clinical entity until 1981.

2. Characterized by
   1. Profound Immunologic deficiencies

   2. opportunistic infections

   3. Uncommon forms of malignant neoplasms

3. The primary expression of HIV is immunodeficiency and the chief mode of recognition (other than lab testing) is development of opportunistic infections.

   

4. The Virus: Human immunodeficiency virus (HIV ). This virus was originally called: 1) Human T-cell lymphotropic virus type-III (HTLV-III) or 2) Lymphadenopathy-associated virus (LAV).

5. All treatments have been unsuccessful in eradicating HIV, however a few treatments have been able to suppress the virus.

6. Research is directed at

   1. Treating associated opportunistic infections

   2. Designing effective immunization

   3. Developing agents to assist in reconstitution of the immune system.

   4. Developing treatments to eradicate the virus.

II. Epidemiology

A. Statistics (American Red Cross, Toledo Chapter, 4/97)

1. Ohio (data through March 31, 1997)

   Lucas County            425 Cases AIDS, 274 Deaths (64%)
   Wood County             35 Cases AIDS, 25 Deaths
   Greater Toledo Area     1000 Estimated HIV +
   NW Ohio                 2000 Estimated HIV+
   Ohio                    8943 Cases AIDS
                           5847 Deaths (65%)
                                   90% Male
                                   10% Female
                           105 Pediatric Cases (<13 yr)
                           14,000 - 20,000 Estimated HIV+
   

2. US
   • Refer to attached CDC press release
   • Incidence among people >12yo declined 6% between 1995 and 1996
   • 15% decline in white gay and bisexual men
   • incidence in heterosexuals increased by 11% in men and 7% in women
   • incidence declined in white caucasions (-13%) and hispanics (-5%)
   • decline in gay and bisexual IVDA (-17% in whites and -13% in African-Americans)

3. Global
   • 1.4 million cases AIDS reported to WHO (19% increase /yr x 2 years)
   • 7.7 million cases AIDS estimated by WHO
   • 3.2 million increase in 1 year
   • 22.4 million estimated living with HIV
   • at least 0.8 million of those are children
   • 27.9 million infections since late 70's
   • projected minimum 30-40 million infections by 2000 (WHO)

III. Etiology

A. Causative Agent

1. AIDS is now unequivocally felt to be caused by infection with HIV.
   • HIV-1 and HIV-2

B. Biologic characteristics and pathophysiology of HIV infection.

1. HIV is single stranded RNA RETROVIRUS

   1. Possesses a novel enzyme, reverse transcriptase, which enables the virus to use host cell m-RNA to make copies of the virus genome, which may be inserted into the host DNA genome. Thus, HIV may remain dormant , to be activated later by an unknown mechanism.

   2. HIV has tropism for specific receptor sites on cells, notably:

      - T4 helper lymphocytes
      - Neural cells of the CNS and spinal cord
      - Monocytes and macrophages

2. Invasion of the cells mentioned above does not always occur.

3. HIV infection of T4 helper cells leads to absolute depression in numbers as well as multiple detects in the immune function of these cells.

C. Transmission

1. Body fluid known to transmit

2. Behaviors or conditions associated with transmission

   • homosexual or heterosexual intercourse (anal, vaginal, oral)
   • IV drug use
   • vertical transmission (pregnancy, delivery, possibly breast feeding)
   • contaminated blood products and transfusions
   • occupational transmission involving health care workers to HIV-infected specimen

3. Blood and transfusion medicine

   • Blood donation
   • Testing history and current risk factors
   • Transfusion alternatives

IV. Serological Testing

A. Terminology

• Confidential
• Anonymous

B. Testing Issues

• Who should be tested?
• When should you be tested?
• Mandatory testing?

B. Assays used

1. Antibody based tests

• ELISA (Enzyme-linked immunosorbent assay
1. Normally a screening assay
2. Not CONCLUSIVE PROOF
3. sensitivity and specificity >99%
• Western Blot
1. Positive result when 2 of the following are present: p24, gp41, and gp120/gp160.
2. 100% specific
3. Used as confirmatory test
4. Small subset of patients not detected.
• Indirect Immunofluorescence Assay (IFA)
1. Used as confirmatory test
2. confirms presence of anti-HIV antibodies in serum

2. Detection of viral antigens

• 'capture' p24 antigen from blood sample and probe it with enzyme labelled HIV antibody

3. Viral Nucleic Acid Detection

• Polymerase Chain Reaction

-Amplicor HIV-1 monitor®
-target amplication
-lower limit of detection 400 copies/ml
• Branched DNA (bDNA)

-Quantiplex® bDNA
-signal amplication
-lower limit of detection 500 copies/ml

4. HIV culture

• highly specific but insensitive means of diagnosing
• success in obtaining a positive culture ranges from 40-97%

5. Rapid Dx, alternative fluids and home collection

• Single-use diagnostic system (SUDS-Murex Diagnostics)
1. detect HIV antibody
2. positive results must be confirm with Western Blot
3. 99.9% sensitive, 99.6% specific (in study)
4. high temp and inadequate centrifugation can lead to false positives
• OraSure (Epitope, SmithKline Beecham)
1. test for HIV antibody in oral fluid
2. must be mailed to lab to tested by ELISA
3. positive results must be confirm with Western Blot
• Calypte (Calypte Biomedical)
1. detects HIV antibodies in urine
2. low sensitivity and specificity
3. no urine Western Blot available to confirm
• Home Access (Home Access Health Care)
1. over the counter kit
2. anonymous testing
3. finger-stick blood sample is sent to central lab for ELISA
4. positive results confirmed with IFA
5. results available in 3-7 days
6. disadvantage-reporting procedure; negative results get recorded message and positive result get a counselor
7. 100% specificity and sensitivity (in study)

V. Disease course

1. Acute infection: Pt may have flu-like symptoms
2. Asymptomatic period: Pt looks and feels well
3. Symptomatic Period Persons may have enlarged lymph glands, tiredness, weight loss, fever, chronic diarrhea, yeast infections, among other conditions
4. AIDS: People with AIDS may have illnesses healthy people usually don't get. They may have more severe version of other illnesses

VI. Prevention

A. Universal precautions and barriers

B. Sexual practices and risk

C. Condom use

VII. Local Resources

SEE ATTACHED SHEET

VIII. Pharmacotherapy

A. Antiviral agents and their pharmacokinetic properties

1. Nucleoside reverse transcriptase inhibitors (NRTI)

1. zidovudine (AZT, Retrovir®)
   • t ½ » 1 hr
   • Oral: F = 65% (1st pass effect)
   • Vd=1.6L/kg
   • PB= 34-38%
   • Eliminated by glomerular filtration and tubular secretion
   • ADR: bone marrow suppression (anemia, granulocytopenia)
   • DI: ganciclovir, interferon a , bone marrow suppressive agents/cytotoxic agents, probenecid, phenytoin, methadone, fluconazole, atovaqone, valproic acid, lamivudine, rifampin
   • Dosing: Adults 600mg/day (in combo with other agents) and 500 mg (100 mg q4h w hile awake) or 600 mg/day for monotherapy. Severe renal impairment: 100 mg q6-8hr ( 300-400mg/day)

2. didanosine (ddI, Videx®)
   • t ½ » 1.6 hr
   • Oral: F =33%
   • Vd=54L
   • renally cleared by glomerular filtration and tubular secretion
   • ADR: pancreatitis, peripheral neuropathy
   • DI: fluoroquinolones, tetracyclines, drug whose absorption is dependent on the level of acidity in the stomach
   • Dosing: Adults: ³ 60kg - 200mg BID (tablets) or 250mg BID (buffered powder) , <60kg- 125mg BID (tablets) or 167 mg BID (buffered powder).
   • Administer on an empty stomach
   • Tablets buffered with duhydroaluminum sodium carbonate, magnesium hydroxide and sodium citrate. Powder for oral solution buffered with dibasic sodium phosphate, sodium citrate, and citric acid.

3. lamivudine (3TC, Epivir®)
   • t ½ » 5-7 hr
   • Oral: F = 86-87%
   • Vd=1.3L/kg
   • PB= <36%
   • renally cleared
   • ADR: (in combo with AZT)Headache, malaise, nausea; monotherapy pancreatitis, parasthesias
   • DI: TMP/SMX
   • Dosing:

   CrCL(ml/min)		Dosage
   									
   GT/=50		150mg twice daily	
   30-49		150mg once daily
   15-29		150mg 1st dose, then 100mg once daily
   5-14		150mg 1st dose, then 50mg once daily
   <5		50mg 1st dose, then 25mg once daily
   		
   

   • For adults with low body weight (50kg or 110 lbs), 2mg/kg twice daily

4. zalcitabine (ddC, Hivid®)
   • t ½ » 2 hr
   • Oral: F >80%
   • Vd=0.534L/kg
   • renally cleared
   • ADR: pancreatitis, peripheral neuropathy
   • DI: antacids, drug associated with peripheral neuropathy, cimetidine, metoclopramide, drug associated with pancreatitis, probenecid
   • Dosing: 0.75mg q8h ( 2.25 mg/day)
   • CrCl 10-40 ml/min then 0.75mg q12h; Crcl <10ml.min then 0.74mg q24h

5. stavudine (d4T, Zerit®)
   • t ½ » 1.44 ± 0.30 hr
   • Oral: F = 86.4 ± 18.2%, rapidly absorbed; dose dependent absorption; not affected by food
   • Vd 66 ± 22L
   • metabolism not elucidated n humans; TBC = 559 ± 168 ml/min; renally clearance is 40% of TBC (tubular secretion and filtration)
   • ADR: dose-related peripheral neuropathy, nonspecific ADR, altered LFTs, neutropenia, thrombocytopenia
   • DI: no information
   • Dosing: 40mg q12h (if ³ 60kg), 30 mg q12h (if < 60kg)
   • Decrease dose by 50% if patient presents with peripheral neuropathy
   • CrCl:

     >50 ml/min then 40mg q12h (if ³ 60kg), 30 mg q12h (if < 60kg)

   
   25-50 ml/min then 20mg q12h (if ³ 60kg), 15 mg q12h (if < 60kg)
   10-25 ml/min then 20mg q24h (if ³ 60kg), 15 mg q24h (if < 60kg)

2. Nonnucleoside reverse transcriptase inhibitors (NNRTI)

1. nevirapine (Viramune®)
   • t ½ » 2 hr
   • Oral: F >90%, not affected by food, fasting, or concomitant administration with antacids or ddI
   • PB= 60%
   • metabolized by cytochrome P450 isoenzymes (inducer)
   • Cleared renally ( of parent and inactive metabolite)
   • autoinduction characteristics
   • ADR: rash (prevention 14 day lead in dosing), fever, nausea, headache, and abnormal liver function tests
   • DI: limted data: caution with hepatically metabolized drugs
   • Dosing: 200 mg qd x14 daysm followed by 200mg bid

2. delaviridine (Rescriptor®)
   • t ½ » 5.8 hr (2-11hr) after 400 mg TID
   • Oral: rapidly absorbed, F (single dose) = 85% ± 25% (increased by 25% when administer by slurry method); not affected by food
   • PB= 98% (albumin)
   • metabolized by cytochrome P450 CYP3A, also CYP2D6(in vitro)
   • nonlinear steady state elimination
   • 51% of dose eliminated renally and 44% eliminated in feces
   • affect of renal and hepatic impairment not studied
   • ADR: rash, nausea, fatigue, headache, and increased liver function tests; neutropenia, anemia, thrombocytopenia
   • DI:
   
   Increased concentration: Protease inhibitors, terfenadine, astemizole, dapsone, rifabutin
   Decreased concentration: carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin,
   Decreased absorption: antacids, didanosine (separate by 1 hour)
   • Dosing: 400 mg TID, can de dispersed in water

3. Protease inhibitors (PI)

1. saquinavir (Invirase®)
   • Oral F = 4%; must be taken with meals ( preferably high fat meals)
   • extensive hepatic metabolism (P450 3A); potent inhibitor of P450 3A4
   • DI: rifampin, rifabutin, terfenadine, astemizole, cisapride
   • best tolerated
   • ADR: diarrhea, nausea, GI discomfort, rash

2. indinavir (Crixivan®)
   • F decreased with meals
   • metabolized by P450 3A4
   • DI: rifampin, rifabutin, terfenadine, astemizole, cisapride, DDI
   • Dosed q8h not TID
   • ADR: nephrolithiasis ( should drink plenty of fluids throughout the day- 1.5L/day), mild GI symptoms

3. ritonavir (Novir®)
   • inhibitor of P450 CYP3A
   • DI: terfenadine, astemizole, cisapride, sedatiuve hypnotics,
   • BID dosing
   • most problematic from a safety and tolerability perspective especially early in trt
   • ADR: mild to moderate- diarrhea, vomiting, nausea, asthenia, anorexia, fatigue, taste disturbance, circumoral paresthesia, increased liver transaminases, creatinine kinase, and triglycerides
   • Dose-escalating regimen: 300mg BID and increased over 1-2 weeks in 100mg increments as tolerated to 600 mg BID. Administering with food decreases S/E

4. nelfinavir (Viracept®)
   • 750mg TID with food
   • DI profile similar to indinavir
   • ADR: loose stools and mild to moderate diarrhea, mild fatigue and poor concentration

B. Treatment (JAMA 1997;277:1962-1969)

1. Considerations for initiating therapy

• Therapy is recommended for all patients with HIV RNA levels > 5,000 to 10,000 copies/ml of plasma
• Therapy is considered for all patients with HIV infected patients with detectable HIV RNA in plasma
• For patients at low risk of progression (low plasma HIV RNA level and high CD4+ counts), particularly those who are not committed to complex antiretroviral regimens, therapy might be safely deferred. These patients should be reevaluated every 3 to 6 months.

2. Options for Initial Therapy

Regimen	Advantages	Disadvantage
NRTI-1 and NRTI-2, and PI	This regimen should be able to achieve plasma HIV RNA levels below limit of detection in large majority of drug adherent patients	Strict adherence to this regimen is crucial; quality of life may be affected; durability of effect, long term tolerance, and overall clinical benefit in antiretrovirall-naive patients with early disease is not fully defined.
NRTI-1 and NRTI-2, and NNRTI	Many patients taking this regimen achieve plasma HIV RNA levels below the limit of detection; it also permits deferral of a PI if this option is chosen	Strict adherence to this regimen is crucial; may not be as potent as PI-containing regimen; it is not recommended for patients with advanced disease (i.e., low CD4+ counts or high plasma viral load); durability of effect and overall clinical benefit not fully defined.

3. Indications for changing therapy

• Treatment failure, as suggested by a confirmed plasma HIV RNA level or failure to achieve the desired reduction in plasma viral load; declining CD4+ cell counts; clinical disease progression.
• Unacceptable toxicity of, intolerance of, nonadherence to the regimen
• Current use of suboptimal treatment regimens, ie, antiretroviral monotherapy

4. Treatment Regimens

A. Triple regimens

Inital Regimen	Alternative Combination
AZT-lamivudine-PI1	Stavudine-DDI-PI2 Stavudine-DDI-NNRTI Ritonavir-Saquinavir-NRTI
Stavudine-lamivudine-PI1	AZT-DDI-PI2 AZT-DDI-NNRTI Ritonavir-Saquinavir-NRTI
AZT-DDI-PI1	Stavudine-lamivudine-PI2 Stavudine-lamivudine- NNRTI Ritonavir-Saquinavir-NRTI
Stavudine-DDI-PI1	AZT- lamivudine -PI2 AZT- lamivudine -NNRTI Ritonavir-Saquinavir-NRTI
AZT-DDI-NNRTI	Stavudine-lamivudine-PI1 AZT- lamivudine -PI2

B. Double drug regimen

Inital Regimen	Alternative Combination
AZT- DDI	AZT- lamivudine -PI Stavudine-lamivudine-PI Ritonavir-Saquinavir-NRTI
Stavudine-zalcitabine	AZT- lamivudine -PI Stavudine-lamivudine-PI Stavudine-DDI-PI Ritonavir-Saquinavir-NRTI
AZT- lamivudine	Stavudine-DDI-PI Ritonavir-Saquinavir-NRTI
Stavudine-DDI	AZT- lamivudine -PI Ritonavir-Saquinavir-NRTI
Stavudine - lamivudine	AZT- DDI -PI2 Ritonavir-Saquinavir-NRTI

C. Postexposure prophylaxis (CDC 1996 Vol 45 No 22)

Type of Exposure	Source material	Antiretroviral prophylaxis	Antiretroviral regimen
Percutaneous	Blood Highest risk Increased risk No increased risk Fluid containing visible blood, other potentially infectious fluid, or tissue Other body fluid (e.g., urine)	Recommended Recommended Offer Offer       Not offer	ZDV + 3TC + IDV ZDV + 3TC ± IDV ZDV + 3TC ZDV + 3TC
Mucous membrane	Blood Fluid containing visible blood, other potentially infectious fluid, or tissue Other body fluid (e.g., urine)	Offer Offer     Not offer	ZDV + 3TC ± IDV ZDV ± 3TC
Skin, increased risk	Blood Fluid containing visible blood, other potentially infectious fluid, or tissue Other body fluid (e.g., urine)	Offer Offer     Not offer	ZDV + 3TC ± IDV ZDV ± 3TC

D. Pregnancy

• AZT indicated for the prevention of maternal-fetal HIV transmission. (ACTG076)

-oral retrovir begininning btw 14 and 34 weeks gestation
-IV retrovir during labor
-syrup to neonate after birth x 6weeks

5. Monitoring

1. CD4 count
   • at diagnosis
   • q 3-6 months thereafter

2. Viral Load
   1. When?
      • At diagnosis
      • q 3-4 months ( to assess to need for therapy)
      • immediately before and 4 weeks after treatment is started ( inital assessment of therapy)
      • 3-4 months after treatment is started ( to assess max benefit of therapy)
      • q 3-4 months during therapy ( to assess persistent antiviral effect)
      • at the time of AIDS related clinical event or if CD4 count declines ( to assess need for treatment change)

6. Reasons for changing therapy

• failure to achieve a reduction in viral load of at least 10 fold after 4 weeks of therapy
• Failure to suppress plasma RNA to undetectable levels within 4-5 months
• Repeated detection of HIV RNA in plasma after the virus was initially suppressed to undetectable levels
• Any reproducible increase in HIV RNA to at least 3x the lowest measurement
• A persistent decline in CD4 T lymphocytes count
• Clinical deterioration

VI. Infectious Complications (MMWR 1997 Vol 46 RR-12)

A. AIDS Defining opportunistic Infections:

B. Recommendations for prophylaxis (MMWR 1997 Vol 46 RR-12)

I. Strongly recommended as standard of care

Pathogen	Indication	1st choice	Alternative
Pneumocystis carinii	CD2+ <200/µl or orophargyngeal candiasis or unexplained fever ³ 2 weeks	TMP-SMZ 1DS po qd; TMP-SMZ 1SS po qd	TMP-SMZ 1DS po TIW; dapsone 50mg po BID or 100 mg po qd; dapsone 50 mg po qw + pyrimethamine 50 mg po qw + leucovorin 25mg po qw; dapsone 200mg po + pyrimethamine 75 mg po qw + leucovorin 25mg po qw; aerosolized pentamidine 300 mg qm via Respirgard II nebulizer
M. tuberculosis INH sensitive           INH resistant   MDR (INH, RFP)	TST reaction ³ 5mm or prior TST result w/o treatment or contact with case of active TB   Same; high probability of exposure to INH resistant TB Same; high probability of exposure to MDR TB	INH 300 mg po + pyridoxine 50 mg po qd x 12 months or INH 900mg po + pyridoxine 50 mg BIW x 12 months Rifampin 600 mg po qd x 12 months   Choice of drugs requires consultant with public health authorities	Rifampin 600 mg po qd x 12 months         Rifabutin 300 mg po qd x 12 months   None
Toxoplasma gondii	IgG Ab to Toxoplasma + CD4 <100/µl	TMP-SMZ 1 DS po qd	TMP-SMZ 1SS po qd; dapsone 50 mg po qw + pyrimethamine 50 mg po qw + leucovorin 25mg po qw;
M. avium complex	CD4 <50m l	Clarithromycin 500 mg po BID or azithromyxcin 1200mg po qw	Rifabutin 300 mg po qd; azithromycin 1200 mg po qw + rifabutin 300 mg po qd
S. pneumoniae	All patients	Pneumococcal vaccine 0.5 ml im x 1 (CD4 ³ 200/µl, CD4<200/µl)	None
Varicella zoster virus	Significant exposure to chickenpox or shingles for patients who have no history of either condition or , if available negative AB to VZV	Varicella zoster immune globulin (VZIG), 5 vials (1.25 ml each) im administered £ 96 h after exposure, ideally within 48 h	Acyclovir 800 mg po 5xD for 3 weeks

II. Generally Recommended

Pathogen	Indication	1st choice	Alternative
Hepatitis B virus	All susceptible ( anti-HBc-negative) patients	Engerix B 20µg im x 3; or Recombivax HB 10µg im x 3		None
Influenza virus	All patients (annually before influenza season)	Whole or split virus, 0.5 ml im/yr		Rimantidine 100 mg po bid or amantadine 100 mg po bid

III. Not recommended for most patients; indicated for use in unusual circumstances

Pathogen	Indication	1st choice	Alternative
Candida species	CD4 <50/µl	Fluconazole 100-200mg po qd
Bacteria	Neutropenia	Granulocyte-colony stimulating factor (G-CSF) 5-10 µg/kg sc qd x 2-4 w or Granulocyte-macrophage colony stimulating factor (GMCSF) 250µg/m2 iv over 2h qd x 2-4 w
Cryptococcus neoformans	CD4<50/µl	Fluconazole 100-200 mg po qd		Itraconazole 200 mg po qd
Histoplasma capsulatum	CD4 <100/µl, endemic geopgraphic area	Itraconazole 200mg po qd		None
Cytomegalovirus (CMV)	CD4 <50/µl and CMV Ab positive	Oral ganciclovir 1 g po tid		None

C. Recommendations for treatment (Pharmacotherapy, A Pathophysiologic Approach. 3rd edition. Chapter 117)

NRTI

Zidovudine ( AZT, ZDV, Retrovir®, GlaxoWellcome) 300mg tablets, 100 mg capsules, 10mg/ml syrup
Lamivudine ( 3TC, Epivir®, GlaxoWellcome) 150mg tablets, 10mg/ml syrup
Zalcitabine (ddC, Hivid®, Roche Laboratories) 0.375, 0.75 mg tablets
Didanosine (ddI, Videx®, Bristol-Myers Squibb) 25,50,100, 150mg chewable tablets; 100, 167, 250, and 375 mg powder for oral solution (buffered); 2g and 4g powder for oral solution (pediatric)
Stavudine (d4T, Zerit®, Bristol-Myers Squibb)

Protease inhibitors

Indinavir (Crixivan®, Merck & Co.) 200 mg and 400mg capsules
Saquinavir (Invirase®, Roche Laboratories)
Ritonavir (Norvir®, Abbott Laboratories)
Nelfinavir (Viracept, Agouron Pharmaceuticals)

NNRTI

Delaviridine (Rescriptor®, Pharmacia & Upjohn)
Nevirapine (Viramune®, Roxane Laboratories) 200mg tablets