"The US Food and Drug Administration (FDA) has approved Gilead Sciences' fixed-dose HIV combination pill Odefsey containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir alafenamide (TAF; 25 mg), the company announced.
Tables 2 and 3 summarize the clinical adverse events and laboratory abnormalities, respectively, that occurred in ≥ 1% of patients in the comparative monotherapy trial (CPCRA 002) of HIVID (zalcitabine) vs didanosine (ddI), and the comparative combination trial (ACTG 175) of zidovudine (ZDV) monotherapy vs HIVID (zalcitabine) and zidovudine combination therapy, respectively. Other studies have found a higher or lower incidence of adverse experiences depending upon disease status, generally being lower in patients with less advanced disease.
Table 2. Percentage of Patients With Clinical Adverse Experience
≥ Grade 3*† in ≥ 1% of Patients Receiving HIVID (zalcitabine)
|CPCRA 002* ZDV Intolerantor Failure||ACTG 175‡ ZDV Naive/Experienced|
|HIVID 0.750 mg q8h
|ddI 250 mg q12h
|ZDV 200 mg q8h
|HIVID + ZDV 0.750 mg q8h + 200 mg q8h
|Body System/Adverse Event|
|Abnormal Hepatic Function||8.9||7.0|||||||||
|Metabolic and Nutrition|
|* Grade 2 Adverse Events possibly or probably
related to treatment or unassessable were included if study drug dosage
was changed or interrupted.
† Grade 3 severity: event possible hospitalization.
Grade 4 severity: completely disabling, unable to care for self, requiring active medical intervention, probable hospitalization or hospice care.
‡ All relationships.
§ Adverse experiences were combined to form this category.
|| See Table 3.
¶ CPCRA 002 included patients who were dose-adjusted for Grade 2 events; ACTG 175 required dose adjustment for Grade 2 peripheral neuropathy but recorded only Grade 3 events.
Table 3. Percentage of Patients With Laboratory Abnormalities
— Protocol Grade 3/4
|CPCRA 002* ZDV Intolerant or Failure||ACTG 175 ZDV Naive/Experienced|
|HIVID 0.750 mg q8h
|ddI 250 mg q12h
|ZDV 200 mg q8h
|HIVID (zalcitabine) +ZDV
0.750 mg q8h+200 mg q8h
|Anemia (<7.5 gm/dL)||8.4||7.4||1.8||3.1|
|Leukopenia (<1500 cells/mm3)||13.1||9.6||N/A||N/A|
|Eosinophilia (>1000 cells/mm3 or 25%)||2.5||1.7||N/A||N/A|
|Neutropenia (<750 cells/mm3)||16.9||11.7||1.9||4.2|
|Thrombocytopenia (<50,000 cells/mm3)||1.3||4.8||1.1||1.8|
|CPK Elevation* (>4 x ULN)||0.8||0.0||5.8||5.7|
|ALT (SGPT) (>5 x ULN)||N/A||N/A||3.6||5.0|
|AST (SGOT) (>5 x ULN)||7.6||5.7||2.9||4.1|
|Bilirubin (>2.5 x ULN)||0.8||0.9||0.5||1.0|
|GGT (>5 x ULN)||N/A||N/A||0.5||1.0|
|Amylase (>2 x ULN)||5.1||3.9||1.0||1.5|
|Hyperglycemia* (>250 mg/dL)||0.0||1.7||0.8||2.0|
|*Grade 3 or higher reported for CPCRA 002.
N/A Not available.
Additional clinical adverse experiences associated with HIVID (zalcitabine) that occurred in < 1% of patients in CPCRA 002 (at least possibly related, Grade 3 or higher), ACTG 175 (any relationship, Grade 3/4) or in other clinical studies are listed below by body system. Several of these events occurred in slightly higher rates in other studies. The incidence of adverse experiences varied in different studies, generally being lower in patients with less-advanced disease.
Body as a Whole: abnormal weight loss, asthenia, cachexia, chest tightness or pain, chills, cutaneous/allergic reaction, debilitation, difficulty moving, dry eyes/mouth, edema, facial pain or swelling, flank pain, flushing, increased sweating, lymphadenopathy, hypersensitivity reactions (see WARNINGS), malaise, night sweats, pain, pelvic/groin pain, rigors, redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Cardiovascular: abnormal cardiac movement, arrhythmia, atrial fibrillation, cardiac failure, cardiac dysrhythmias, cardiomyopathy, heart racing, hypertension, palpitation, subarachnoid hemorrhage, syncope, tachycardia, ventricular ectopy.
Endocrine/Metabolic: abnormal triglycerides, abnormal lipase, altered serum glucose, decreased bicarbonate, diabetes mellitus, glycosuria, gout, hot flushes, hypercalcemia, hyperkalemia, hyperlipemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, increased nonprotein nitrogen, lactic acidosis.
Gastrointestinal:abdominal bloating or cramps, acute pancreatitis, anal/rectal pain, anorexia, bleeding gums, bloody or black stools, colitis, dental abscess, dry mouth, dyspepsia, dysphagia, enlarged abdomen, epigastric pain, eructation, esophageal pain, esophageal ulcers, esophagitis, flatulence, gagging with pills, gastritis, gastrointestinal hemorrhage, gingivitis, glossitis, gum disorder, heartburn, hemorrhagic pancreatitis, hemorrhoids, increased saliva, left quadrant pain, melena, mouth lesion, odynophagia, painful sore gums, painful swallowing, pancreatitis, rectal hemorrhage, rectal mass, rectal ulcers, salivary gland enlargement, sore tongue, sore throat, tongue disorder, tongue ulcer, toothache, unformed/loose stools, vomiting.
Hematologic: absolute neutrophil count alteration, anemia, epistaxis, decreased hematocrit, granulocytosis, hemoglobinemia, leukopenia, neutrophilia, platelet alteration, purpura, thrombus, unspecified hematologic toxicity, white blood cell alteration.
Musculoskeletal: arthralgia, arthritis, arthropathy, arthrosis, back pain, backache, bone pains/aches, bursitis, cold extremities, extremity pain, joint inflammation, leg cramps, muscle aches, muscle weakness, muscle disorder, muscle stiffness, muscle cramps, myalgia, myopathy, myositis, neck pain, rib pain, stiff neck.
Neurological: abnormal coordination, aphasia, ataxia, Bell's palsy, confusion, decreased concentration, decreased neurological function, disequilibrium, dizziness, dysphonia, facial nerve palsy, focal motor seizures, grand mal seizure, hyperkinesia, hypertonia, hypokinesia, memory loss, migraine, neuralgia, neuritis, paralysis, seizures, speech disorder, status epilepticus, stupor, tremor, twitch, vertigo.
Psychological:acute psychotic disorder, acute stress reaction, agitation, amnesia, anxiety, confusion, decreased motivation, decreased sexual desire, depersonalization, emotional lability, euphoria, hallucination, impaired concentration, insomnia, manic reaction, mood swings, nervousness, paranoid state, somnolence, suicide attempt, dementia.
Respiratory: acute nasopharyngitis, chest congestion, coughing, cyanosis, difficulty breathing, dry nasal mucosa, dyspnea, flu-like symptoms, hemoptysis, nasal discharge, pharyngitis, rales/rhonchi, respiratory distress, sinus congestion, sinus pain, sinusitis, wheezing.
Skin: acne, alopecia, bullous eruptions, carbuncle/furuncle, cellulitis, cold sore, dermatitis, dry skin, dry rash desquamation, erythematous rash, exfoliative dermatitis, finger inflammation, follicular rash, impetigo, infection, itchy rash, lip blisters/lesions, macular/papular rash, maculopapular rash, moniliasis, mucocutaneous/skin disorder, nail disorder, photosensitivity reaction, pruritic disorder, pruritus, skin disorder, skin lesions, skin fissure, skin ulcer, urticaria.
Special Senses: abnormal vision, blurred vision, burning eyes, decreased taste, decreased vision, ear pain/problem, ear blockage, eye abnormality, eye inflammation, eye itching, eye pain, eye irritation, eye redness, eye hemorrhage, fluid in ears, hearing loss, increased tears, loss of taste, mucopurulent conjunctivitis, parosmia, photophobia, smell dysfunction, taste perversion, tinnitus, unequal-sized pupils, xerophthalmia, yellow sclera.
Urogenital: abnormal renal function, acute renal failure, albuminuria, bladder pain, dysuria, frequent urination, genital lesion/ulcer, increased blood urea nitrogen, increased creatinine, micturition frequency, nocturia, painful penis sore, pain on urination, penile edema, polyuria, renal cyst, renal calculus, testicular swelling, toxic nephropathy, urinary retention, vaginal itch, vaginal ulcer, vaginal pain, vaginal/cervix disorder, vaginal discharge.
Read the Hivid (zalcitabine) Side Effects Center for a complete guide to possible side effects
Zidovudine: There is no significant pharmacokinetic interaction between ZDV and zalcitabine which has been confirmed clinically. Zalcitabine also has no significant effect on the intracellular phosphorylation of ZDV, as shown in vitro in peripheral blood mononuclear cells or in two other cell lines (U937 and Molt-4). In the same study it was shown that didanosine and stavudine had no significant effect on the intracellular phosphorylation of zalcitabine in peripheral blood mononuclear cells.
Lamivudine: In vitro studies in peripheral blood mononuclear cells, U937 and Molt-4 cells revealed that lamivudine significantly inhibited zalcitabine phosphorylation in a dose dependent manner. Effects were already seen with doses corresponding to relevant plasma levels in humans, and the intracellular phosphorylation of zalcitabine to its three metabolites (including the active zalcitabine triphosphate metabolite) was significantly inhibited. Zalcitabine inhibited lamivudine phosphorylation at high concentration ratios (10 and 100); however, it is considered to be unlikely that this decrease of phosphorylated lamivudine concentration is of clinical significance, as lamivudine is a more efficient substrate for deoxycytidine kinase than zalcitabine. These in vitro studies suggest that concomitant administration of zalcitabine and lamivudine in humans may result in sub-therapeutic concentrations of active phosphorylated zalcitabine, which may lead to a decreased antiretroviral effect of zalcitabine. It is unknown how the effect seen in these in vitro studies translates into clinical consequences.
Concomitant use of zalcitabine and lamivudine is not recommended.
Saquinavir: The combination of HIVID (zalcitabine) , saquinavir, and ZDV has been studied (as triple combination) in adults. Pharmacokinetic data suggest that absorption, metabolism, and elimination of each of these drugs are unchanged when they are used together.
Drugs Associated With Peripheral Neuropathy: The concomitant use of HIVID (zalcitabine) with drugs that have the potential to cause peripheral neuropathy should be avoided where possible. Drugs that have been associated with peripheral neuropathy include antiretroviral nucleoside analogues, chloramphenicol, cisplatin, dapsone, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, and vincristine. Concomitant use of HIVID (zalcitabine) with didanosine is not recommended.
Intravenous Pentamidine: Treatment with HIVID (zalcitabine) should be interrupted when the use of a drug that has the potential to cause pancreatitis is required. Death due to fulminant pancreatitis possibly related to intravenous pentamidine and HIVID (zalcitabine) has been reported. If intravenous pentamidine is required to treat Pneumocystis carinii pneumonia, treatment with HIVID should be interrupted (see WARNINGS).
Amphotericin, Foscarnet, and Aminoglycosides: Drugs such as amphotericin, foscarnet, and aminoglycosides may increase the risk of developing peripheral neuropathy (see WARNINGS: Peripheral Neuropathy) or other HIVID (zalcitabine) -associated adverse events by interfering with the renal clearance of zalcitabine (thereby raising systemic exposure). Patients who require the use of one of these drugs with HIVID (zalcitabine) should have frequent clinical and laboratory monitoring with dosage adjustment for any significant change in renal function.
Probenecid or Cimetidine: Concomitant administration of probenecid or cimetidine decreases the elimination of zalcitabine, most likely by inhibition of renal tubular secretion of zalcitabine. Patients receiving these drugs in combination with zalcitabine should be monitored for signs of toxicity and the dose of zalcitabine reduced if warranted.
Magnesium/Aluminum-containing Antacid Products: Absorption of zalcitabine is moderately reduced (approximately 25%) when coadministered with magnesium/aluminum-containing antacid products. The clinical significance of this reduction is not known, hence zalcitabine is not recommended to be ingested simultaneously with magnesium/aluminum-containing antacids.
Metoclopramide: Bioavailability is mildly reduced (approximately 10%) when zalcitabine and metoclopramide are coadministered (see CLINICAL PHARMACOLOGY: Drug Interactions).
Doxorubicin: Doxorubicin caused a decrease in zalcitabine phosphorylation ( > 50% inhibition of total phosphate formation) in U937/Molt 4 cells. Although there may be decreased zalcitabine activity because of lessened active metabolite formation, the clinical relevance of these in vitro results are not known.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/30/2009
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