Kaletra: profile and news

Cipher receives Health Canada approval of CIP-Fenofibrate Feb 20, 2006
20 /CNW/ - Cipher Pharmaceuticals Inc. (TSX: DND) today announced that it has received final approval from Health Canada for CIP-Fenofibrate, the Company's ... - Canada NewsWire (press release),

Cipher reports fiscal 2005 year-end results Mar 2, 2006
2005 Summary and Subsequent Events ----- Received final approval in the US and Canada for CIP-FENOFIBRATE, subsequent to ... - Canada NewsWire (press release),

(PRN) - Cipher receives Health Canada approval of CIP-Fenofibrate ... Feb 20, 2006
...(PRN) - Graham Packaging Responds to Consumer Preferences in Design of Innovative Safe-T-Can(TM) for Basic American Foods ... [+. ... - Bolsamania.com,

Cipher receives Health Canada approval of CIP-Fenofibrate Feb 20, 2006
...(TSX: DND - News) today announced that it has received final approval from Health Canada for CIP-Fenofibrate, the Company's novel formulation of the active ... - Yahoo! News (press release)

Cipher receives Health Canada approval of CIP-Fenofibrate Feb 21, 2006
...today announced that it has received final approval from Health Canada for CIP-Fenofibrate, the Company's novel formulation of the active ingredient fenofibrate ... - PharmaLive.com (press release),

Cipher Pharmaceuticals gets Canadian approval for anti-cholesterol ... Feb 20, 2006
The Mississauga, Ont.-based firm's shares spiked in mid-January when it announced its formulation of fenofibrate, CIP-Fenofibrate, had received final US ... - Calgary Sun,

CROI: Fish oil and fibrate combination reduces blood fats in HIV ... Feb 10, 2006
HIV-positive patients with elevated blood triglyceride levels may benefit from a combination of fish oil and fenofibrate if they have failed to respond to ... - Aidsmap,

Notice of Cipher Pharmaceuticals Inc. Conference Call Feb 28, 2006
The Company's lead compound, CIP-FENOFIBRATE, received final approval from the US Food and Drug Administration and Health Canada in the first quarter of 2006. ... - Canada NewsWire (press release),

SCOLR Pharma Reports Positive Ondansetron Clinical Results, New ... Feb 16, 2006
...to two new drug targets. The new targets include developing novel formulations of fenofibrate and gabapentin. Our goal with these ... - Genetic Engineering News,

Consiga la Gold Card American Express ahora Feb 20, 2006
...[+]. (PRN) - Tax and Financial Group, Petersen Earn Securian Awards ... [+. PRN) - Cipher receives Health Canada approval of CIP-Fenofibrate ... [+. ... - Bolsamania.com,

CROI: Lipodystrophy stable in children on HIV treatment and does ... Feb 23, 2006
Although ten of the patients received treatment with recombinant human growth hormone or fenofibrate (Lipantil / Supralip 160), only one of these patients ... - Aidsmap,

Solvay says core profit up 20 pct in Q4 Feb 16, 2006
Fournier contributed 265 million euros in sales and 64 million euros in REBIT, Solvay said, adding that sales of Fournier's fenofibrate anti-chlorestorol drug ... - Reuters

Solvay FY net up 51 pct to 816 mln eur from 541 mln UPDATE Feb 16, 2006
302 mln eur. Solvay said that the performance of Fournier's fenofibrate was 'remarkable' and above its expectations. The company ... - Forbes

Do Lackluster Trial Findings Mean New Avenues Are Needed for Heart ... Feb 9, 2006
The failure of fenofibrate to reduce fatal myocardial infarctions and other heart-related deaths in people with type 2 diabetes (Keech A et al. Lancet. ... - Journal of American Medical Association (subscription),

The Lowdown on High Triglycerides Feb 14, 2006
...you take niacin. Fibrates, which include gemfibrozil (Lopid) and fenofibrate (Tricor), are an alternative to niacin. They reduce ... - Gilroy Dispatch (subscription),

New Records for Solvay in 2005, After Excellent Results in 2004 Feb 16, 2006
64 million. The performance of fenofibrate, Fournier PharmaтАЩs тАЬblockbuster,тА? was remarkable and above our expectations. The ... - PharmaLive.com (press release),

Statins may not affect CD4 cell count responses to HIV treatment ... Feb 1, 2006
In contrast, they prescribed the 103 patients (39%) with raised triglyceride levels either bezafibrate (Bezalip), fenofibrate (Lipantil) or gemfibrozil (Lopid ... - Aidsmap,

Cipher receives FDA approval for CIP-Fenofibrate Jan 13, 2006
...(TSX: DND) today announced that it has received final approval from the US Food and Drug Administration (FDA) for CIP-Fenofibrate, the Company's novel ... - PR Newswire (press release),

Cipher receives FDA approval for Lipofen (CIP-Fenofibrate) Jan 13, 2006
...today announced that it has received final approval from the US Food and Drug Administration (FDA) for CIP-Fenofibrate, the Company's novel formulation of the ... - DG News

Cipher Pharmaceuticals shares spike 50% after FDA nod for ... Jan 13, 2006
...almost 53 per cent, to close at $2.78 on the Toronto stock market as the Mississauga, Ont.-based company said its formulation of fenofibrate, CIP-Fenofibrate ... - CBC News,

Cipher Pharmaceuticals gets FDA nod for hyperlipidemia drug ... Jan 13, 2006
Cipher spiked 98 cents, almost 54 per cent, to $2.80 in morning trading on the Toronto Stock Exchange after it announced that CIP-Fenofibrate, its formulation ... - Calgary Sun,

Cipher Pharmaceuticals shares spike 50% after FDA nod for ... Jan 13, 2006
...cent, to $2.80 in mid-afternoon trading on the Toronto stock market as the Mississauga, Ont.-based company said its formulation of fenofibrate, CIP-Fenofibrate ... - Canada.com,

No Significant Effects on the Pharmacokinetics of a Single Dose of ... Jan 19, 2006
...by First Horizon Pharmaceutical Corporation found no significant effects on the pharmacokinetics of a single dose of Triglide (fenofibrate) Tablets when ... - DG News

Cipher shares soar on drug approval Jan 13, 2006
...in Cipher rose 96 cents to close at $2.78 on the Toronto stock market as the Mississauga-based company said its formulation of fenofibrate, CIP-Fenofibrate ... - Toronto Star,

Open-Label Study Shows No Significant Effects on the ... Jan 19, 2006
Zocor** (simvastatin) and Lipitor*** (atorvastatin calcium) on the pharmacokinetics and safety of a single dose of TRIGLIDE(TM) (fenofibrate) tablets in 20 ... - Biotech Intelligence (press release),

Cipher shares soar on US approval of drug Jan 14, 2006
...drug. The Mississauga-based company said its formulation of fenofibrate, CIP-Fenofibrate, was approved under the label Lipofen. ... - Globe and Mail,

FDA OK's Cipher's cholesterol drug Jan 13, 2006
Cipher said Lipofen is a novel formulation of the active ingredient fenofibrate, used to treat high cholesterol in the bloodstream. ... - United Press International

Cipher Provides CIP-Tramadol ER Update Jan 27, 2006
The Company's lead compound, CIP-Fenofibrate, received final approval from the US Food and Drug Administration in January 2006. ... - International News Service,

First Horizon Evaluates Triglide Drug Combo Jan 26, 2006
Lipitor (atorvastatin calcium), and Kos Pharmaceuticals' Niaspan (niacin) on the pharmacokinetics and safety of a single dose of Triglide (fenofibrate) tablets ... - International News Service,

Abbott shares rise on Q4 and Guidant win Jan 26, 2006
Solid growth during the period was also supported by: the cholesterol-buster TriCor (fenofibrate), up 37.5% to $312 million; the antibiotic Omnicef (cefdinir ... - Pharma Times (subscription),

(PRN) - Webcast Alert: AMCOL International Announces 4th Quarter ... Jan 13, 2006
...(PRN) - Third Wave, Digene Dismiss HPV Patent Suit ... [+. PRN) - Cipher receives FDA approval for CIP-Fenofibrate ... [+. PRN ... - Bolsamania.com,

(PRN) - Atlantic Southern Financial Group, Inc. Reports Record ... Jan 19, 2006
...[+]. (PRN) - Open-Label Study Shows No Significant Effects on the Pharmacokinetics of a Single Dose of TRIGLIDE(TM) (Fenofibrate) Tablets When Combined With ... - Bolsamania.com,

Other information

Indication
Indicated in combination with other antiretroviral agents for the treatment of HIV-infection.

Pharmacology
Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Ritonavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

Mechanism Of Action
Ritonavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.

Drug Category
Anti-HIV Agents; HIV Protease Inhibitors; ATC:J05AE03

Brand Names/Synonyms
Abbott 84538; Kaletra; Norvir; Norvir Sec; Ritonavir; Ritonavir [Usan]

Dosage Forms
CAPSULE (100 mg); SOLUTION (80 mg/mL of ritonavir)

Absorption
The absolute bioavailability of ritonavir has not been determined.

Interactions
-->Interactions for Ritonavir:

Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo (Table 2). Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (>3-fold) when co-administered with ritonavir. Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A as well as other enzymes, including glucuronosyl transferase, CYP1A2, and possibly CYP2C9.

Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed both in CONTRAINDICATIONS Table 3 and under Contraindicated Drugs in Table 4.

Those drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY , Table 2. The clinical recommendations based on the results of these studies are listed in Table 4 Established Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies.

A systematic review of over 200 medications prescribed to HIV-infected patients was performed to identify potential drug interactions with ritonavir. ² There are a number of agents in which CYP3A or CYP2D6 partially contribute to the metabolism of the agent. In these cases, the magnitude of the interaction and therapeutic consequences cannot be predicted with any certainty.

When co-administering ritonavir with calcium channel blockers, immunosuppressants, some HMG-CoA reductase inhibitors, some steroids, or other substrates of CYP3A, or most antidepressants, certain antiarrhythmics, and some narcotic analgesics which are partially mediated by CYP2D6 metabolism, it is possible that substantial increases in concentrations of these other agents may occur, possibly requiring a dosage reduction (>50%); examples are listed in Table 4 Predicted Drug Interactions: Use With Caution, Dose Decrease May be Needed.

When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations.

**Table 4**
**Drug Interactions With NORVIR**
**CONTRAINDICATED DRUGS**
**(Same as Table 3)**
DRUGS THAT ARE CONTRAINDICATED WITH NORVIR USE
Drug Class	Drugs Within Class That Are CONTRAINDICATED With NORVIR
Antiarrhythmics	amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines	astemizole, terfenadine
Antimigraine	dihydroergotamine, ergotamine
Sedative/hypnotics	midazolam, triazolam
GI motility agent	cisapride
Neuroleptic	pimozide

Established Drug Interactions: Alteration in Dose or
Regimen Recommended Based
on Drug Interaction Studies
Drug Name	Effect	Clinical Comment
Clarithromycin	up clarithromycin concentration	For patients with renal impairment the following dosage adjustments should be considered: · For patients with CL _CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. · For patients with CL _CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Desipramine	up desipramine concentration	Dosage reduction and concentration monitoring of desipramine is recommended
Didanosine		Dosing of didanosine and ritonavir should be separated by 2.5 hours to avoid formulation incompatibility
Disulfiram/Metronidazole		Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole)
Indinavir	up indinavir concentration	Appropriate doses for this combination, with respect to efficacy and safety, have not been established
Ketoconazole	up ketoconazole concentration	High doses of ketoconazole (>200 mg/day) are not recommended
Meperidine	down meperidine concentration/ up normeperidine concentration (metabolite)	Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures)
Methadone	down methadone concentration	Dosage increase of methadone may be considered
Oral Contraceptives	down ethinyl estradiol concentration	Dosage increase or alternate contraceptive measures should be considered
Rifabutin	up rifabutin and rifabutin metabolite concentration	Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg/day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary
Rifampin	down ritonavir concentration	Alternate antimycobacterial agents such as rifabutin should be considered
Saquinavir	up saquinavir concentration	When used in combination therapy for up to 24 weeks, doses of 400 mg b.i.d. of ritonavir and saquinavir were better tolerated than the higher doses of the combination. Saquinavir plasma concentrations achieved with Invirase® (saquinavir mesylate) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.) are similar to those achieved with Fortovaseô (saquinavir) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.)
Sildenafil	up sildenafil concentration	Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period in patients receiving concomitant ritonavir therapy
Theophylline	down theophylline concentration	Increased dosage of theophylline may be required; therapeutic monitoring should be considered

Predicted Drug Interactions: Use With Caution, Dose Decrease of Coadministered Drug May Be Needed
Examples of Drugs in Which Plasma Concentrations May Be Increased By Co-Administration With NORVIR
Drug Class	Examples of Drugs
Analgesics, narcotic	tramadol, propoxyphene
Antiarrhythmics	disopyramide, lidocaine, mexilitine
Anticonvulsants	carbamazepine, clonazepam, ethosuximide
Antidepressants	bupropion, nefazodone, selective serotonin reuptake inhibitors (SSRIs), tricyclics
Antiemetics	dronabinol
Antiparasitics	quinine
(beta)-blockers	metoprolol, timolol
Calcium channel blockers	diltiazem, nifedipine, verapamil
Hypolipidemics, HMG CoA reductase inhibitors ¹	atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants	cyclosporine, tacrolimus
Neuroleptics	perphenazine, risperidone, thioridazine
Sedative/hypnotics	clorazepate, diazepam, estazolam, flurazepam, zolpidem
Steroids	dexamethasone, prednisone
Stimulants	methamphetamine
¹ Coadministration with lovastatin and simvastatin is not recommended.
Predicted Drug Interactions: Use With Caution, Dose Increase of Coadministered Drug May Be Needed
Examples of Drugs in Which Plasma Concentrations May Be Decreased By Co-Administration With NORVIR
Anticoagulants	warfarin
Anticonvulsants	phenytoin, divalproex, lamotrigine
Antiparasitics	atovaquone

Post-Marketing Experience with Drugs Listed in Table 4

Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.

Chemical IUPAC Name
1,3-thiazol-5-ylmethyl [3-hydroxy-5-[3-methyl-2-[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino-butanoyl]amino-1,6-diphenyl-hexan-2-yl]aminoformate

Chemical Formula
C37H48N6O5S2

Half Life
3-5 hours

Drug Type
Approved Drug

# Accession No
APRD00312

CAS Registry Number
155213-67-5