izing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions;
Metabolic: hyperglycemia, glycosuria, hyperuricemia;
Musculoskeletal: muscle spasm;
Nervous System/Psychiatric: restlessness;
Renal: renal failure, renal dysfunction, interstitial nephritis;
Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis;
Special Senses: transient blurred vision, xanthopsia.
Initial Therapy - Hypertension
In a clinical study in patients with severe hypertension (diastolic blood pressure ≥110mmHg and systolic blood pressure ≥140mmHg), the overall pattern of adverse reactions reported through six weeks of follow-up was similar in patients treated with DiovanHCT as initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with DiovanHCT (force-titrated to 320/25mg) and valsartan (force-titrated to 320mg), dizziness was observed in6% and 2% of patients, respectively. Hypotension was observed in 1% of those patients receiving DiovanHCT and 0% of patients receiving valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with DiovanHCT as initial therapy in patients with severe hypertension were similar to those reported with DiovanHCT in patients with less severe hypertension [see Clinical Studies (14.2) and Drug Interactions(7.3)].
6.2 Postmarketing Experience
The following additional adverse reactions have been reported in valsartan or valsartan/hydrochlorothiazidepostmarketing experience:
Hypersensitivity: There are rare reports of angioedema;
Digestive: Elevated liver enzymes and very rare reports of hepatitis;
Renal: Impaired renal function;
Clinical Laboratory Tests: Hyperkalemia;
Dermatologic: Alopecia;
Vascular: Vasculitis;
Nervous System: Syncope.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
7 DRUG INTERACTIONS
Valsartan: No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide,or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely because of low extent of metabolism [see Pharmacokinetics (12.3)].
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
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